Wearable automatic injection device for controlled delivery of therapeutic agents

ABSTRACT

Exemplary embodiments provide wearable automatic injection devices for subcutaneously injecting a therapeutic agent into a patient&#39;s body at controlled rates, for example, in a single bolus. Exemplary embodiments provide methods for assembling wearable automatic injection devices for subcutaneously injecting a therapeutic agent into a patient&#39;s body at controlled rates. Exemplary embodiments provide methods for using wearable automatic injection devices for subcutaneously injecting a therapeutic agent into a patient&#39;s body at controlled rates.

RELATED APPLICATIONS

This application is related to and claims priority to U.S. ProvisionalApplication Ser. No. 61/326,637, filed Apr. 21, 2010, the entirecontents of which are expressly incorporated herein by reference intheir entirety.

BACKGROUND

Automatic injection devices offer an alternative to manually-operatedsyringes for delivering therapeutic agents into patients' bodies andallowing patients to self-administer injections. Automatic injectiondevices have been used to deliver medications under emergencyconditions, for example, to administer epinephrine to counteract theeffects of a severe allergic reaction. Automatic injection devices havealso been described for use in administering anti-arrhythmic medicationsand selective thrombolytic agents during a heart attack (See, e.g., U.S.Pat. Nos. 3,910,260; 4,004,577; 4,689,042; 4,755,169; and 4,795,433).Various types of automatic injection devices are also described in, forexample, U.S. Pat. Nos. 3,941,130; 4,261,358; 5,085,642; 5,092,843;5,102,393; 5,267,963; 6,149,626; 6,270,479; and 6,371,939; andInternational Patent Publication No. WO/2008/005315.

Conventionally, an automatic injection device houses a syringe and, whenoperated, causes the syringe to move forwardly and a needle to projectfrom the housing so that a therapeutic agent contained in the syringe isejected into a patient's skin. An automatic injection device typicallyincludes a bung disposed within the syringe that, when actuated, moveswithin the syringe to expel the therapeutic agent from the syringe andinto the patient's skin.

SUMMARY

Exemplary embodiments provide wearable automatic injection devices thatmay adhere to the skin or clothing of a patient and deliver atherapeutic agent into the patient's body by subcutaneous injection atslow, controlled injection rates, e.g., in a single slow bolus.Exemplary embodiments provide methods of assembling exemplary wearableautomatic injection devices. Exemplary embodiments also provide methodsof using wearable automatic injection devices worn by a patient forslow, controlled therapeutic agent delivery. Exemplary wearableautomatic injection devices reduce or eliminate a burning sensationoften felt or perceived by patients who use a conventional automaticinjection device. Exemplary wearable automatic injection devicesmaintain the sterility of the therapeutic agent container (e.g.,syringe), are easy to use, pre-fill capable, easy to manufacture, and/ordo not require aseptic assembly. The wearable automatic injectiondevices provided by exemplary embodiments may adhere to the skin orclothing of the patient to deliver any therapeutic agent subcutaneouslyincluding, but not limited to, a biologic drug, such as, for example, anantibody, insulin, etc.

In accordance with an exemplary embodiment, a wearable automaticinjection device is provided for providing a subcutaneous injection of atherapeutic agent into a patient. The device includes a housingcomprising a patient contact portion securable to the patient. Thedevice also includes an injection assembly moveably disposed in thehousing holding a hypodermic injection needle for insertion into thepatient, the injection assembly moveable between a retracted position inwhich the injection needle does not protrude outside the housing and anextended position in which the injection needle protrudes outside thehousing. The device also includes a vessel provided in the housing forholding the therapeutic agent, a plunger moveably disposed in the vesselfor ejecting the therapeutic agent from the vessel into the injectionassembly, and a plunger actuation mechanism for actuating the plungerwithin the vessel. The device also includes a retraction triggerresponsive to a change of state of the wearable automatic injectiondevice from an injection state to a post-injection state, and aretraction mechanism for automatically retracting the injection assemblyfrom the extended position in the injection state to the retractedposition in the post-injection state upon triggering by the retractiontrigger.

In accordance with another exemplary embodiment, a method is providedfor subcutaneously injecting a therapeutic agent into a patient. Themethod includes providing a wearable automatic injection deviceincluding a housing comprising a patient contact portion securable tothe patient. The device also includes an injection assembly moveablydisposed in the housing holding a hypodermic injection needle forinsertion into the patient, the injection assembly moveable between aretracted position in which the injection needle does not protrudeoutside the housing and an extended position in which the injectionneedle protrudes outside the housing. The device also includes a vesselprovided in the housing for holding the therapeutic agent, a plungermoveably disposed in the vessel for ejecting the therapeutic agent fromthe vessel into the injection assembly, and a plunger actuationmechanism for actuating the plunger within the vessel. The device alsoincludes a retraction trigger responsive to a change of state of thewearable automatic injection device from an injection state to apost-injection state, and a retraction mechanism for automaticallyretracting the injection assembly from the extended position in theinjection state to the retracted position in the post-injection stateupon triggering by the retraction trigger. The method includes securingthe wearable automatic injection device to the skin of the patient or anarticle of clothing on the patient using the patient contact of thehousing. The method also includes administering the therapeutic agentinto the skin of the patient using the wearable automatic injectiondevice.

In accordance with another exemplary embodiment, a wearable automaticinjection device is provided for subcutaneously injecting a therapeuticagent into a patient. The device includes a housing and a cartridgeassembly movably disposed within the housing. The cartridge includes abarrel portion for holding the therapeutic agent, and a hollow needle influid communication with the barrel portion for ejecting the therapeuticagent from the barrel portion. The cartridge also includes a bung forsealing the barrel portion and selectively applying pressure to thetherapeutic agent to force the therapeutic agent through the hollowneedle. The cartridge further includes a plunger actuator for applyingpressure to the bung, and a trigger mechanism that actuates the plungeractuator to apply pressure to the bung when the cartridge is depressedfrom a ready position (in a pre-injection state) to a depressed position(in an injection state) inside the housing. The trigger mechanismactuates the plunger actuator such that the therapeutic agent is ejectedfrom the barrel portion and into the patient at a controlled, slow ratewith little or no burning sensation felt or perceived by the patient.The device also includes a fastener layer disposed on a patient contactsurface to fasten the device to the skin or clothing of the patient orto an article of clothing of the patient. The fastener layer may includean adhesive for temporarily securing the wearable automatic injectiondevice to the patient at least during the controlled injection of thetherapeutic agent.

The wearable automatic injection device includes a retraction mechanismthat retracts the cartridge from the depressed position to a retractedposition (in a post-injection state). The wearable automatic injectiondevice also includes a retraction trigger that activates the retractionmechanism, the retraction trigger trips when delivery of the therapeuticagent completes, or times out due an elapsed period of time, or when thewearable automatic injection device is removed from the patient, forexample, before delivery of the therapeutic agent is completed. Thewearable automatic injection device operates and functions entirely onmechanical principles or in combination with a controlled reaction totransition from any state (i.e., a pre-injection state, an injectionstate, a post-injection state), and controls the injection rate of thetherapeutic agent over a time period that is selected for patientcomfort, convenience or preference, or exceeds a time period forinjection by a conventional automatic handheld device. In an exemplaryembodiment, the time period of the injection by an exemplary wearableautomatic injection device may range between about ten seconds and abouttwelve hours. In a preferred embodiment, the time period may rangebetween about five minutes and about thirty minutes.

In another exemplary embodiment, a method is provided for subcutaneouslyinjecting a therapeutic agent into a patient. The method includesproviding a wearable automatic injection device comprising a housing anda cartridge assembly movably disposed within the housing. The cartridgeincludes a barrel portion for holding a therapeutic agent, and a hollowneedle in fluid communication with the barrel portion for ejecting thetherapeutic agent from the barrel portion. The cartridge also includes abung for sealing the barrel portion and selectively applying pressure tothe therapeutic agent to force the therapeutic agent through the hollowneedle. The cartridge further includes a plunger actuator for applyingpressure to the bung, and a trigger mechanism that actuates the plungeractuator to apply pressure to the bung when the cartridge is depressedfrom a ready position (in a pre-injection state) to a depressed position(in an injection state) inside the housing. The trigger mechanismactuates the plunger actuator such that the therapeutic agent is ejectedfrom the barrel portion and into the patient at a controlled, slow rateand substantially free of any burning sensation.

The method also includes depressing the cartridge from the readyposition to a depressed position within the housing. Depressing thecartridge automatically causes the injection needle that is used topierce the patient's skin to project from an opening in the housing topenetrate the skin of the patient, and actuates the plunger actuator toapply pressure to the bung such that the therapeutic agent is deliveredinto the patient at a controlled, slow rate and substantially free ofany burning sensation.

The method further includes automatically retracting the cartridge fromthe depressed to a retracted position (in a post-injection state) in thehousing when delivery of the therapeutic agent is completed, or timesout due to an elapsed period of time, or when the wearable automaticinjection device is removed from the skin or clothing of the patient,for example, before delivery of the therapeutic agent is completed.

In an exemplary embodiment, a wearable automatic injection device isprovided. The wearable automatic injection device provides asubcutaneous injection of a therapeutic agent into a patient. Thewearable automatic injection device includes a housing having a patientcontact portion securable to the patient and an interior portion definedby a plurality of walls and defining at least one open end opposing thepatient contact portion. The wearable automatic injection device alsoincludes a cartridge assembly movably disposed within the interiorportion of the housing and movable from any of a ready position, aninjection position, and a retraction position. The wearable automaticinjection device further includes a trigger mechanism responsive to achange in state of the wearable automatic injection device from apre-injection state to an injection state to actuate a plunger actuatordisposed in the cartridge assembly to begin ejection of a therapeuticagent from the cartridge assembly, and a retraction trigger responsiveto a change of state of the wearable automatic injection device from theinjection state to a post-injection state. The wearable automaticinjection device also includes a retraction mechanism responsive to theretraction trigger to automatically retract the cartridge assembly fromthe patient when the automatic injection device enters thepost-injection state.

In another exemplary embodiment, a method of subcutaneously injecting atherapeutic agent into a patient is provided. The method includessecuring to a patient a wearable automatic injection device comprising ahousing having a patient contact portion securable to the patient and aninterior portion defined by a plurality of walls and defining at leastone open end opposing the patient contact portion and a cartridgeassembly movably disposed within the interior portion of the housing andmovable from any of a ready position, an injection position, and aretraction position, the cartridge assembly holding the therapeuticagent in a pre-fillable and/or pre-filled sterile manner. The methodalso includes depressing the cartridge assembly downwardly towards thepatient contact portion to cause the wearable automatic injection deviceto enter an injection state from a pre-injection state to automaticallyproject a needle from a needle aperture in the housing and penetrate theskin of the patient and expel the therapeutic agent into the patient ata controlled rate.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, aspects, features, and advantages ofexemplary embodiments will become more apparent and may be betterunderstood by referring to the following description taken inconjunction with the accompanying drawings, in which:

FIG. 1A illustrates a first end view and a first side view of anexemplary wearable device including a cartridge assembly in a packagedpre-injection state.

FIG. 1B illustrates the first end view and the first side view of theexemplary device of FIG. 1A before an injection in a pre-injection statein which a needle cover covering the injection needle is removed inpreparation for an injection.

FIG. 1C illustrates the first end view and the first side view of theexemplary device of FIG. 1A during an injection in an injection state inwhich the patient's skin is pierced by the injection needle.

FIG. 1D illustrates the first end view and the first side view of theexemplary device of FIG. 1A during an injection in an injection state inwhich a barrel portion of the device containing a dose of thetherapeutic agent is deployed forwardly within the housing of thedevice.

FIG. 1E illustrates the first end view and the first side view of theexemplary device of FIG. 1A during an injection in an injection state inwhich a bung of the device is actuated by a plunger actuator to expelthe dose of the therapeutic agent from the barrel portion.

FIG. 1F illustrates the first end view and the first side view of theexemplary device of FIG. 1A after an injection in a post-injection statein which the injection needle is retracted within the housing of thedevice.

FIG. 2A illustrates a first end view and a first side view of anexemplary wearable device including a syringe assembly in a packagedpre-injection state.

FIG. 2B illustrates the first end view and the first side view of theexemplary device of FIG. 2A before an injection in a pre-injection statein which a needle cover covering the injection needle is removed inpreparation for an injection.

FIG. 2C illustrates the first end view and the first side view of theexemplary device of FIG. 2A during an injection in an injection state inwhich the patient's skin is pierced by the injection needle.

FIG. 2D illustrates the first end view and the first side view of theexemplary device of FIG. 2A during an injection in an injection state inwhich a barrel portion of the device containing a dose of thetherapeutic agent is deployed forwardly within the housing of thedevice.

FIG. 2E illustrates the first end view and the first side view of theexemplary device of FIG. 2A during an injection in an injection state inwhich a bung of the device is actuated by a plunger actuator to expelthe dose of the therapeutic agent from the barrel portion.

FIG. 2F illustrates the first end view and the first side view of theexemplary device of FIG. 2A after an injection in a post-injection statein which the injection needle is retracted within the housing of thedevice.

FIG. 3 is a flow chart of an exemplary method of assembling an exemplarywearable automatic injection device.

FIG. 4 is a flow chart of an exemplary method of using an exemplaryautomatic wearable injection device.

FIG. 5 is a flow chart of an exemplary method of using an exemplarywearable automatic injection device to inject a therapeutic agent into apatient.

FIG. 6A illustrates an exemplary wearable automatic injection devicesuitable for linear insertion into a patient in a pre-injection state.

FIG. 6B illustrates the exemplary device of FIG. 6A in an injectionstate ready to inject or injecting a dose of a therapeutic agent into apatient.

FIG. 6C illustrates the exemplary device of FIGS. 6A and 6B in a postinjection state after it has completed injecting the therapeutic agentinto the patient or removed from the patient prior to completion of theinjecting of the therapeutic agent.

FIG. 7A illustrates an exemplary wearable automatic injection devicesuitable for rotary insertion in a pre-injection state ready for use bya patient.

FIG. 7B illustrates the exemplary device of FIG. 7A in an injectionstate ready to inject or injecting a dose of a therapeutic agent into apatient.

FIG. 7C illustrates the exemplary device of FIGS. 7A and 7B in apost-injection state after it has completed injecting the therapeuticagent into the patient or removed from the patient prior to completionof the injecting of the therapeutic agent.

FIG. 8 is a flow chart of an exemplary method of assembling an exemplarywearable automatic injection device.

FIG. 9 is a flow chart of an exemplary method of using an exemplarywearable automatic injection device.

FIG. 10 is a flow chart of an exemplary method of using an exemplarywearable automatic injection device to inject a therapeutic agent into apatient.

FIG. 11 illustrates an exemplary barrel portion in which a distal end ofthe barrel portion bears an injection needle that extends substantiallyalong the longitudinal axis of the barrel portion.

FIG. 12 illustrates an exemplary barrel portion in which a distal end ofthe barrel portion bears an injection needle that extends at about 90degrees relative to the longitudinal axis of the barrel portion.

FIG. 13 illustrates an exemplary needle assembly in which an exemplaryadapter couples a syringe needle to an injection needle.

FIG. 14 illustrates an exemplary needle assembly in which a fluidconduit couples a syringe needle to an injection needle.

FIG. 15 illustrates an exemplary transfer mechanism for providing afluid conduit between a syringe needle and an injection needle.

FIG. 16 illustrates an exemplary transfer mechanism for providing afluid conduit between a syringe needle and an injection needle.

FIG. 17 illustrates an exemplary transfer mechanism for providing afluid conduit between a syringe needle and an injection needle.

FIG. 18A illustrates a perspective view of an exemplary wearableautomatic injection device.

FIG. 18B illustrates a disassembled view showing the components of theexemplary device of FIG. 18A.

FIG. 19A illustrates a side view of an exemplary wearable automaticinjection device.

FIG. 19B illustrates a perspective view showing the components of thedevice of FIG. 19A.

FIG. 20A illustrates a perspective view of an exemplary wearableautomatic injection device.

FIG. 20B illustrates a top view of the device of FIG. 20A.

FIG. 20C illustrates a side view of the transfer mechanism of the deviceof FIG. 20A.

FIG. 21A illustrates a perspective view of an exemplary wearableautomatic injection device including an exemplary cartridge assembly.

FIG. 21B illustrates a sectional view of the exemplary cartridgeassembly of FIG. 21A taken along a longitudinal axis.

FIG. 21C illustrates a transparent top view of the exemplary device ofFIG. 21A.

FIG. 22 illustrates an exemplary syringe or cartridge actuator that maybe used to advance a barrel portion and/or the cartridge assembly from aretraction position to an extended position within the housing of awearable automatic injection device.

FIG. 23 illustrates an exemplary syringe or cartridge actuator includinga first portion, a second portion and a hinge portion provided betweenthe first and second portions.

FIG. 24 illustrates a schematic of a portion of an exemplary automaticinjection device including a plunger actuation mechanism that employs afusee and a viscous damping mechanism.

FIG. 25 illustrates a wearable automatic injection device may include aplatform, a slideable carriage coupled to the platform, and a cartridgeassembly mounted on the slideable carriage.

FIG. 26 illustrates a wearable automatic injection device may include aplatform, a slideable carriage coupled to the platform, and a cartridgeassembly mounted on the slideable carriage.

FIG. 27 is a top view through a cover of an exemplary automaticinjection device including a plunger actuation mechanism forautomatically actuating a bung in a barrel portion.

FIG. 28 is a side view of the exemplary automatic injection device ofFIG. 27 showing a fusee and a damping mechanism.

FIG. 29 is a perspective view through a cover of the exemplary automaticinjection device of FIG. 27.

FIG. 30 illustrates x and y coordinates (in inches) of cam profiles for:(i) the combination of spring 1 and a viscous damper, (ii) thecombination of spring 1 and an escapement, (iii) the combination ofspring 2 and a viscous damper, and (iv) the combination of spring 2 andan escapement.

FIG. 31 illustrates a graph of therapeutic agent flow rates (inmilliliters per minute) versus time (in seconds) delivered by: (i) thecombination of spring 1 and a viscous damper, (ii) the combination ofspring 1, a viscous damper and a cam spool, (iii) the combination ofspring 1 and an escapement, (iv) the combination of spring 1, anescapement and a cam spool, (v) the combination of spring 2 and aviscous damper, (vi) the combination of spring 2, a viscous damper and acam spool, (vii) the combination of spring 2 and an escapement, (viii)the combination of spring 2, an escapement and a cam spool, and (ix) andan ideal flow rate in which the therapeutic agent is delivered at asubstantially constant rate.

FIG. 32 illustrates a graph of the volume of therapeutic agent (inmilliliters) versus time (in seconds) delivered by the combinations ofcomponents of FIG. 31.

FIG. 33 illustrates a graph of the volume of therapeutic agent (inmilliliters) against time (in seconds) delivered using: (i) a G dampingmechanism having a damping coefficient of about 10.3 lbf*s/in with agear ratio of 4:1, (ii) a B damping mechanism having a dampingcoefficient of about 15.1 lbf*s/in with a gear ratio of 4:1, (iii) a Kdamping mechanism having a damping coefficient of about 18.9 lbf*s/inwith a gear ratio of 4:1, (iv) a V damping mechanism having a dampingcoefficient of about 24.9 lbf*s/in with a gear ratio of 4:1, (v) a Gdamping mechanism having a damping coefficient of about 25.1 lbf*s/inwith a gear ratio of 6.25:1, (vi) a B damping mechanism having a dampingcoefficient of about 37.0 lbf*s/in with a gear ratio of 6.25:1, (vii) aK damping mechanism having a damping coefficient of about 46.2 lbf*s/inwith a gear ratio of 6.25:1, (viii) a V damping mechanism having adamping coefficient of about 60.7 lbf*s/in with a gear ratio of 6.25:1,(ix) a G damping mechanism having a damping coefficient of about 164lbf*s/in with a gear ratio of 16:1, (x) a B damping mechanism having adamping coefficient of about 242 lbf*s/in with a gear ratio of 16:1,(xi) a K damping mechanism having a damping coefficient of about 303lbf*s/in with a gear ratio of 16:1, (xii) a V damping mechanism having adamping coefficient of about 398 lbf*s/in with a gear ratio of 16:1, and(xiii) an ideal flow rate in which the therapeutic agent is delivered ata substantially constant rate.

FIG. 34 illustrates a graph of exemplary damper torques (that may beback-calculated from the displacement of the plunger actuator) againstdamper speeds (in rpm) for G, B, K and V model dampers having increasingdamping coefficients.

FIG. 35 illustrates a graph of the volume of therapeutic agent (inmilliliters) against time (in seconds) delivered by different exemplarysyringes using a V model damper having a damping coefficient of about24.9 lbf*s/in and an exemplary gear ratio of 4:1.

FIG. 36 illustrates a graph of the volume of therapeutic agent (inmilliliters) delivered and the diameter of the fusee or cam spool (ininches) versus the time (in seconds).

FIG. 37 illustrates a graph of the volume of therapeutic agent (inmilliliters) delivered versus time (in seconds) achieved by: (i) a firstdamper at room temperature, (ii) the first damper at about 40 degreesFahrenheit (in a refrigerator), (iii) a second damper, (iv) the seconddamper at about 0 degree Fahrenheit (in a freezer), (v) a third damperhaving manufacturing variability relative to the first and seconddampers, and (vi) a fourth damper having manufacturing variabilityrelative to the first and second dampers.

FIG. 38 illustrates a schematic of a portion of an exemplary automaticinjection device including a plunger actuation mechanism that employs afusee and an escapement mechanism.

FIG. 39 illustrates an exemplary plunger actuation mechanism thatemploys one or more linear biasing mechanism to provide a force forexpressing a therapeutic agent from the barrel portion of a wearableautomatic injection device.

FIG. 40 illustrates an exemplary plunger actuation mechanism thatemploys one or more clock springs to provide a force for expressing atherapeutic agent from the barrel portion of a wearable automaticinjection device.

FIG. 41 is a schematic of an exemplary automatic injection deviceincluding a plunger actuation mechanism that employs one or more fluidcircuits.

FIG. 42 is an exemplary automatic injection device that employs one ormore fluid circuits to perspective view a force to a bung for expressinga dose of a therapeutic agent from a barrel portion.

FIG. 43 illustrates a graph of the cumulative amount of therapeuticagent (in grams) against time (in seconds) as delivered by an exemplarydelivery system at an exemplary delivery pressure of about 16.5 psi.

FIG. 44 illustrates a graph of the cumulative volume of therapeuticagent (in milliliters) against time (in seconds) as delivered by anexemplary delivery system including a first flow restrictor.

FIG. 45 illustrates a graph of the cumulative volume of therapeuticagent (in milliliters) against time (in seconds) as delivered by anexemplary delivery system including a second flow restrictor.

FIG. 46 is a schematic drawing of an exemplary automatic injectiondevice that employs one or more fluid circuits to provide a force forexpressing a therapeutic agent from a cartridge assembly.

FIG. 47 is a top view of the exemplary device of FIG. 46.

FIG. 48 illustrates a top view of an exemplary automatic injectiondevice which shows a conduit coupling the master cylinder to a flowrestrictor, a conduit coupling the flow restrictor to the bung, and aconduit coupling the master cylinder to a retraction mechanism via avalve.

FIG. 49 illustrates a schematic diagram of the device of FIG. 48.

FIG. 50 illustrates a graph of the pressure after a check valve andbehind a bung (in psi) versus time (in seconds) in an exemplaryembodiment.

FIG. 51 illustrates a side view of an exemplary automatic injectiondevice in which the housing of the wearable automatic injection deviceincludes a skin sensor foot.

FIGS. 52A and 52B illustrate an exemplary needle protection system thatmaintains an injection needle in a retracted position within a housingof an exemplary automatic injection system.

FIGS. 53A and 53B illustrate another exemplary needle protection systemprovided in an exemplary automatic injection system.

FIG. 54 illustrates another exemplary needle protection system providedin of an exemplary automatic injection system.

FIG. 55 illustrates another exemplary needle protection system providedin an exemplary automatic injection system.

DETAILED DESCRIPTION

Subcutaneous injection is a primary mode of therapeutic agent deliveryand involves administering a bolus of a therapeutic agent into apatient. Subcutaneous injections are highly effective in administeringvarious therapeutic agents including insulin, vaccines, and drugs suchas morphine. Automatic injection devices offer an alternative to asyringe for delivering a therapeutic agent and allow patients toself-administer subcutaneous injections of therapeutic agents.Conventional automatic injection devices include hand held automaticinjection devices and patch pumps, which are self-adhesive,patient-mounted auto-injectors. In use, a patch pump containing atherapeutic agent is mounted onto the skin or clothing of a patient andtriggered to inject the therapeutic agent into the patient. Conventionalpatch pumps are typically filled by a patient prior to use. In addition,certain conventional patch pumps have an exposed needle inside the pump,and thus require secondary sterile packaging to maintain sterility.

Studies have shown that there is a direct correlation between theinjection rate of certain therapeutic agents and the pain perceived by apatient upon injection of the therapeutic agents or agents. Sometherapeutic agents cause pain, e.g., a burning or stinging sensationwhen injected rapidly into the patient. The pain sensation may be theresult of a physiological response of the patient's skin to thesubcutaneous injection of a therapeutic agent. Large volumes of anytherapeutic agent, greater than one milliliter, may also cause pain wheninjected into the skin. Antibodies, and portions thereof, are exemplarytherapeutic agents that are least painful when delivered at slowinjection rates. Currently, there are no commercially viableconventional patch pumps that effectively address the discomfortassociated with fast injection rates of hand held automatic injectiondevices.

Exemplary embodiments are described below with reference to certainillustrative embodiments. While exemplary embodiments are described withrespect to using a wearable automatic injection device to provide aninjection of a dose of a liquid medication, one of ordinary skill in theart will recognize that exemplary embodiments are not limited to theillustrative embodiments and that exemplary automatic injection devicesmay be used to inject any suitable substance into a patient. Inaddition, components of exemplary automatic injection devices andmethods of making and using exemplary automatic injection devices arenot limited to the illustrative embodiments described below.

A syringe assembly of exemplary automatic injections devices may containa dose of a TNFa inhibitor. In an exemplary embodiment, the TNFainhibitor may be a human TNFa antibody or antigen-biding portionthereof. In an exemplary embodiment, the human TNFa antibody orantigen-binding portion thereof may be adalimumab or golimumab.

Exemplary embodiments provide wearable automatic injection devices thatmay adhere to the skin or clothing of the patient and deliver atherapeutic agent into patient by subcutaneous injection at slow,controlled injection rates, e.g., in a single slow bolus. The slow,controlled injection rates achieved by exemplary devices minimize thepain sensation associated with a volume of a therapeutic agent enteringinto the patent's tissue. Exemplary time durations for slow deliveryachieved by exemplary devices may range from about 5 minutes to about 30minutes, but are not limited to this exemplary range. Exemplary volumesof therapeutic agent deliverable by exemplary devices may range fromabout 0.8 milliliters to about 1 milliliter, but are not limited to thisexemplary range. In addition, exemplary devices may advantageouslyminimize inflections in the delivery profile against time of thetherapeutic agent.

Exemplary embodiments minimize the size envelope of exemplary automaticinjection devices, and provide scalable solutions with configurabledelivery times and delivery profiles that may be used for a range oftherapeutic agent viscosities.

Exemplary embodiments provide wearable automatic injection devices thatdeliver a therapeutic agent into a patient by subcutaneous injection atslow, controlled injection rates, e.g., in a single slow bolus withoutbattery power or other components requiring electrical current or chargeto operate. Exemplary embodiments also provide methods of using thewearable automatic injection devices for slow, controlled therapeuticagent delivery. The wearable automatic injection devices provided byexemplary embodiments are pre fillable prior to delivery to the patient,maintain sterility of the therapeutic agent and all subcutaneous contactsurfaces (i.e., a hypodermic needle and one or more septums) to avoidthe need for aseptic assembly and address the perceived patientdiscomfort due to injection by conventional hand held automaticinjection devices. Exemplary wearable automatic injection devicesinclude a primary therapeutic barrel portion that maintains sterilityand therefore requires no aseptic assembly. Exemplary wearable automaticinjection devices are disposable, easy to use, pre-fill capable, and maysubstantially or completely eliminate the burning sensation oftenexperienced by a patient that uses a wearable automatic injectiondevice. The wearable automatic injection devices provided by exemplaryembodiments can be used to deliver any therapeutic agent that may bedelivered subcutaneously including, but not limited to, an antibody orinsulin, etc.

I. DEFINITIONS

Certain terms are defined in this section to facilitate understanding ofexemplary embodiments.

The wearable automatic injection device of exemplary embodiments mayinclude a “therapeutically effective amount” or a “prophylacticallyeffective amount” of an antibody or antibody portion of the invention. A“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount of the antibody,antibody portion, or other TNFα inhibitor may vary according to factorssuch as the disease state, age, sex, and weight of the patient, and theability of the antibody, antibody portion, or other TNFα inhibitor toelicit a desired response in the patient. A therapeutically effectiveamount is also one in which any toxic or detrimental effects of theantibody, antibody portion, or other TNFα inhibitor are outweighed bythe therapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result. Typically,since a prophylactic dose is used in patients prior to or at an earlierstage of disease, the prophylactically effective amount will be lessthan the therapeutically effective amount.

The terms “substance” and “therapeutic agent” refer to any type of drug,biologically active agent, biological substance, chemical substance orbiochemical substance that is capable of being administered in atherapeutically effective amount to a patient employing exemplaryautomatic injection devices. Exemplary substances include, but are notlimited to, agents in a liquid state. Such agents may include, but arenot limited to, adalimumab (HUMIRA®) and proteins that are in a liquidsolution, e.g., fusion proteins and enzymes. Examples of proteins insolution include, but are not limited to, Pulmozyme (Dornase alfa),Regranex (Becaplermin), Activase (Alteplase), Aldurazyme (Laronidase),Amevive (Alefacept), Aranesp (Darbepoetin alfa), BecaplerminConcentrate, Betaseron (Interferon beta-1b), BOTOX (Botulinum Toxin TypeA), Elitek (Rasburicase), Elspar (Asparaginase), Epogen (Epoetin alfa),Enbrel (Etanercept), Fabrazyme (Agalsidase beta), Infergen (Interferonalfacon-1), Intron A (Interferon alfa-2a), Kineret (Anakinra), MYOBLOC(Botulinum Toxin Type B), Neulasta (Pegfilgrastim), Neumega(Oprelvekin), Neupogen (Filgrastim), Ontak (Denileukin diftitox),PEGASYS (Peginterferon alfa-2a), Proleukin (Aldesleukin), Pulmozyme(Dornase alfa), Rebif (Interferon beta-1a), Regranex (Becaplermin),Retavase (Reteplase), Roferon-A (Interferon alfa-2), TNKase(Tenecteplase), and Xigris (Drotrecogin alfa), Arcalyst (Rilonacept),NPlate (Romiplostim), Mircera (methoxypolyethylene glycol-epoetin beta),Cinryze (C1 esterase inhibitor), Elaprase (idursulfase), Myozyme(alglucosidase alfa), Orencia (abatacept), Naglazyme (galsulfase),Kepivance (palifermin) and Actimmune (interferon gamma-1b).

A protein in solution may also be an immunoglobulin or antigen-bindingfragment thereof, such as an antibody or antigen-binding portionthereof. Examples of antibodies that may be used in an exemplaryautomatic injection device include, but are not limited to, chimericantibodies, non-human antibodies, human antibodies, humanizedantibodies, and domain antibodies (dAbs). In an exemplary embodiment,the immunoglobulin or antigen-binding fragment thereof, is an anti-TNFaand/or an anti-IL-12 antibody (e.g., it may be a dual variable domainimmunoglobulin (DVD) IgTM). Other examples of immunoglobulins orantigen-binding fragments thereof that may be used in the methods andcompositions of exemplary embodiments include, but are not limited to,1D4.7 (anti-IL-12/IL-23 antibody; Abbott Laboratories); 2.5(E)mg1(anti-IL-18; Abbott Laboratories); 13C5.5 (anti-IL-13 antibody; AbbottLaboratories); J695 (anti-IL-12; Abbott Laboratories); Afelimomab (Fab 2anti-TNF; Abbott Laboratories); HUMIRA (adalimumab) AbbottLaboratories); Campath (Alemtuzumab); CEA-Scan Arcitumomab (fabfragment); Erbitux (Cetuximab); Herceptin (Trastuzumab); Myoscint(Imciromab Pentetate); ProstaScint (Capromab Pendetide); Remicade(Infliximab); ReoPro (Abciximab); Rituxan (Rituximab); Simulect(Basiliximab); Synagis (Palivizumab); Verluma (Nofetumomab); Xolair(Omalizumab); Zenapax (Daclizumab); Zevalin (Ibritumomab Tiuxetan);Orthoclone OKT3 (Muromonab-CD3); Panorex (Edrecolomab); Mylotarg(Gemtuzumab ozogamicin); golimumab (Centocor); Cimzia (Certolizumabpegol); Soliris (Eculizumab); CNTO 1275 (ustekinumab); Vectibix(panitumumab); Bexxar (tositumomab and 1131 tositumomab); and Avastin(bevacizumab).

Additional examples of immunoglobulins, or antigen-binding fragmentsthereof, that may be used in the methods and compositions of exemplaryembodiments include, but are not limited to, proteins comprising one ormore of the following: the D2E7 light chain variable region (SEQ ID NO:1), the D2E7 heavy chain variable region (SEQ ID NO: 2), the D2E7 lightchain variable region CDR3 (SEQ ID NO: 3), the D2E7 heavy chain variableregion CDR3 (SEQ ID NO:4), the D2E7 light chain variable region CDR2(SEQ ID NO: 5), the D2E7 heavy chain variable region CDR2 (SEQ ID NO:6), the D2E7 light chain variable region CDR1 (SEQ ID NO: 7), the D2E7heavy chain variable region CDR1 (SEQ ID NO: 8), the 2SD4 light chainvariable region (SEQ ID NO: 9), the 2SD4 heavy chain variable region(SEQ ID NO: 10), the 2SD4 light chain variable CDR3 (SEQ ID NO: 11), theEP B12 light chain variable CDR3 (SEQ ID NO: 12), the VL10E4 light chainvariable CDR3 (SEQ ID NO: 13), the VL100A9 light chain variable CDR3(SEQ ID NO: 14), the VLL100D2 light chain variable CDR3 (SEQ ID NO: 15),the VLLOF4 light chain variable CDR3 (SEQ ID NO: 16), the LOES lightchain variable CDR3 (SEQ ID NO: 17), the VLLOG7 light chain variableCDR3 (SEQ ID NO: 18), the VLLOG9 light chain variable CDR3 (SEQ ID NO:19), the VLLOH1 light chain variable CDR3 (SEQ ID NO: 20), the VLLOH10light chain variable CDR3 (SEQ ID NO: 21), the VL1B7 light chainvariable CDR3 (SEQ ID NO: 22), the VL1C1 light chain variable CDR3 (SEQID NO: 23), the VL0.1F4 light chain variable CDR3 (SEQ ID NO: 24), theVL0.1H8 light chain variable CDR3 (SEQ ID NO: 25), the LOE7. A lightchain variable CDR3 (SEQ ID NO: 26), the 2SD4 heavy chain variableregion CDR (SEQ ID NO: 27), the VH1B11 heavy chain variable region CDR(SEQ ID NO: 28), the VH1D8 heavy chain variable region CDR (SEQ ID NO:29), the VH1A11 heavy chain variable region CDR (SEQ ID NO: 30), theVH1B12 heavy chain variable region CDR (SEQ ID NO: 31), the VH1E4 heavychain variable region CDR (SEQ ID NO: 32), the VH1F6 heavy chainvariable region CDR (SEQ ID NO: 33), the 3C-H2 heavy chain variableregion CDR (SEQ ID NO: 34), and the VH1-D2.N heavy chain variable regionCDR (SEQ ID NO: 35).

The term “human TNFα” (abbreviated herein as hTNFα, or simply hTNF)refers to a human cytokine that exists as a 17 kD secreted form and a 26kD membrane associated form, the biologically active form of which iscomposed of a trimer of noncovalently bound 17 kD molecules. Thestructure of hTNFα is described further in, for example, Pennica, D., etal. (1984) Nature 312:724-729; Davis, J. M., et al. (1987) Biochem.26:1322-1326; and Jones, E. Y., et al. (1989) Nature 338:225-228. Theterm human TNFα is intended to include recombinant human TNFα (rhTNFα),which can be prepared by standard recombinant expression methods orpurchased commercially (R & D Systems, Catalog No. 210-TA, Minneapolis,Minn.). TNFα is also referred to as TNF. The term “TNFα inhibitor”refers to an agent that interferes with TNFα activity. The term alsoincludes each of the anti-TNFα human antibodies (used interchangeablyherein with TNFα antibodies) and antibody portions described herein aswell as those described in U.S. Pat. Nos. 6,090,382; 6,258,562;6,509,015; 7,223,394; and 6,509,015. In one embodiment, the TNFαinhibitor used in the invention is an anti-TNFα antibody, or a fragmentthereof, including infliximab (Remicade®, Johnson and Johnson; describedin U.S. Pat. No. 5,656,272); CDP571 (a humanized monoclonalanti-TNF-alpha IgG4 antibody); CDP 870 (a humanized monoclonalanti-TNF-alpha antibody fragment); an anti-TNF dAb (Peptech); CNTO 148(golimumab; Centocor, See WO 02/12502 and U.S. Pat. No. 7,521,206 andU.S. Pat. No. 7,250,165); and adalimumab (HUMIRA® Abbott Laboratories, ahuman anti-TNF mAb, described in U.S. Pat. No. 6,090,382 as D2E7).Additional TNF antibodies that may be used in the invention aredescribed in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and6,448,380. In another embodiment, the TNFα inhibitor is a TNF fusionprotein, e.g., etanercept (Enbrel®, Amgen; described in WO 91/03553 andWO 09/406476). In another embodiment, the TNFα inhibitor is arecombinant TNF binding protein (r-TBP-I) (Serono).

In one embodiment, the term “TNFα inhibitor” excludes infliximab. In oneembodiment, the term “TNFα inhibitor” excludes adalimumab. In anotherembodiment, the term “TNFα inhibitor” excludes adalimumab andinfliximab.

In one embodiment, the term “TNFα inhibitor” excludes etanercept, and,optionally, adalimumab, infliximab, and adalimumab and infliximab.

In one embodiment, the term “TNFα antibody” excludes infliximab. In oneembodiment, the term “TNFα antibody” excludes adalimumab. In anotherembodiment, the term “TNFα antibody” excludes adalimumab and infliximab.

The term “antibody” refers to immunoglobulin molecules generallycomprised of four polypeptide chains, two heavy (H) chains and two light(L) chains inter-connected by disulfide bonds. Each heavy chain iscomprised of a heavy chain variable region (abbreviated herein as HCVRor VH) and a heavy chain constant region. The heavy chain constantregion is comprised of three domains, CH1, CH2 and CH3. Each light chainis comprised of a light chain variable region (abbreviated herein asLCVR or VL) and a light chain constant region. The light chain constantregion is comprised of one domain, CL. The VH and VL regions can befurther subdivided into regions of hypervariability, termedcomplementarity determining regions (CDR), interspersed with regionsthat are more conserved, termed framework regions (FR). Each VH and VLis composed of three CDRs and four FRs, arranged from amino-terminus tocarboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3,CDR3, FR4. The antibodies of the invention are described in furtherdetail in U.S. Pat. Nos. 6,090,382; 6,258,562; and 6,509,015.

The term “antigen-binding portion” of an antibody (or simply “antibodyportion”) refers to one or more fragments of an antibody that retain theability to specifically bind to an antigen (e.g., hTNFα). Fragments of afull-length antibody can perform the antigen-binding function of anantibody. Examples of binding fragments encompassed within the term“antigen-binding portion” of an antibody include (i) a Fab fragment, amonovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) aF(ab′)2 fragment, a bivalent fragment comprising two Fab fragmentslinked by a disulfide bridge at the hinge region; (iii) a Fd fragmentconsisting of the VH and CH1 domains; (iv) a Fv fragment consisting ofthe VL and VH domains of a single arm of an antibody, (v) a dAb fragment(Ward et al. (1989) Nature 341:544-546), which consists of a VH or VLdomain; (vi) an isolated complementarity determining region (CDR); and(vii) a dual variable domain immunoglobulin (DVD-Ig). Furthermore,although the two domains of the Fv fragment, VL and VH, are coded for byseparate genes, they can be joined, using recombinant methods, by asynthetic linker that enables them to be made as a single protein chainin which the VL and VH regions pair to form monovalent molecules (knownas single chain Fv (scFv); See e.g., Bird et al. (1988) Science242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA85:5879-5883). Such single chain antibodies are also encompassed withinthe term “antigen-binding portion” of an antibody. Other forms of singlechain antibodies, such as diabodies are also encompassed. Diabodies arebivalent, bispecific antibodies in which VH and VL domains are expressedon a single polypeptide chain, but using a linker that is too short toallow for pairing between the two domains on the same chain, therebyforcing the domains to pair with complementary domains of another chainand creating two antigen binding sites (See e.g., Holliger et al. (1993)Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure2:1121-1123). The antibody portions of the invention are described infurther detail in U.S. Pat. Nos. 6,090,382; 6,258,562; and 6,509,015.

The term “recombinant human antibody” refers to all human antibodiesthat are prepared, expressed, created or isolated by recombinant means,such as antibodies expressed using a recombinant expression vectortransfected into a host cell (described further below), antibodiesisolated from a recombinant, combinatorial human antibody library(described further below), antibodies isolated from an animal (e.g., amouse) that is transgenic for human immunoglobulin genes (See e.g.,Taylor et al. (1992) Nucl. Acids Res. 20:6287) or antibodies prepared,expressed, created or isolated by any other means that involves splicingof human immunoglobulin gene sequences to other DNA sequences. Suchrecombinant human antibodies have variable and constant regions derivedfrom human germ line immunoglobulin sequences. In certain embodiments,however, such recombinant human antibodies are subjected to in vitromutagenesis (or, when an animal transgenic for human Ig sequences isused, in vivo somatic mutagenesis) and thus the amino acid sequences ofthe VH and VL regions of the recombinant antibodies are sequences that,while derived from and related to human germ line VH and VL sequences,may not naturally exist within the human antibody germ line repertoirein vivo.

Such chimeric, humanized, human, and dual specific antibodies can beproduced by recombinant DNA techniques known in the art, for exampleusing methods described in PCT International Application No.PCT/US86/02269; European Patent Application No. 184,187; European PatentApplication No. 171,496; European Patent Application No. 173,494; PCTInternational Publication No. WO 86/01533; U.S. Pat. No. 4,816,567;European Patent Application No. 125,023; Better et al. (1988) Science240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al.(1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987)Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; Shaw etal. (1988) J. Natl. Cancer Inst. 80:1553-1559; Morrison (1985) Science229:1202-1207; Oi et al. (1986) BioTechniques 4:214; U.S. Pat. No.5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al.(1988) Science 239:1534; and Beidler et al. (1988) J. Immunol.141:4053-4060, Queen et al. (1989) Proc. Natl. Acad. Sci. USA86:10029-10033 (1989); U.S. Pat. No. 5,530,101; U.S. Pat. No. 5,585,089;U.S. Pat. No. 5,693,761; U.S. Pat. No. 5,693,762; WO 90/07861; and U.S.Pat. No. 5,225,539.

The term “isolated antibody” refers to an antibody that is substantiallyfree of other antibodies having different antigenic specificities (e.g.,an isolated antibody that specifically binds hTNFα and is substantiallyfree of antibodies that specifically bind antigens other than hTNFα). Anisolated antibody that specifically binds hTNFα may havecross-reactivity to other antigens, such as TNFα molecules from otherspecies. Moreover, an isolated antibody may be substantially free ofother cellular material and/or chemicals.

The term “neutralizing antibody” (or an “antibody that neutralized hTNFαactivity”) refers to an antibody whose binding to hTNFα results ininhibition of the biological activity of hTNFα. This inhibition of thebiological activity of hTNFα can be assessed by measuring one or moreindicators of hTNFα biological activity, such as hTNFα-inducedcytotoxicity (either in vitro or in vivo), hTNFα-induced cellularactivation and hTNFα binding to hTNFα receptors. These indicators ofhTNFα biological activity can be assessed by one or more of severalstandard in vitro or in vivo assays known in the art (See U.S. Pat. No.6,090,382). Preferably, the ability of an antibody to neutralize hTNFαactivity is assessed by inhibition of hTNFα-induced cytotoxicity of L929cells. As an additional or alternative parameter of hTNFα activity, theability of an antibody to inhibit hTNFα-induced expression of ELAM-1 onHUVEC, as a measure of hTNFα-induced cellular activation, can beassessed.

The term “surface plasmon resonance” refers to an optical phenomenonthat allows for the analysis of real-time biospecific interactions bydetection of alterations in protein concentrations within a biosensormatrix, for example using the BIAcore system (Pharmacia Biosensor AB,Uppsala, Sweden and Piscataway, N.J.). For further descriptions, seeExample 1 of U.S. Pat. No. 6,258,562 and Jonsson et al. (1993) Ann.Biol. Clin. 51:19; Jonsson et al. (1991) Biotechniques 11:620-627;Johnsson et al. (1995) J. Mol. Recognit. 8:125; and Johnnson et al.(1991) Anal. Biochem. 198:268.

The term “Koff” refers to the off rate constant for dissociation of anantibody from the antibody/antigen complex.

The term “Kd” refers to the dissociation constant of a particularantibody-antigen interaction.

The term “IC50” refers to the concentration of the inhibitor required toinhibit the biological endpoint of interest, e.g., neutralizecytotoxicity activity.

The term “dose” or “dosage” refers to an amount of a substance, such asa TNFα inhibitor, which is administered to a patient preferably usingthe wearable automatic injection device of the invention. In oneembodiment, the dose comprises an effective amount, for example,including, but not limited to, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg,80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, and 160mg, of the TNFα inhibitor adalimumab.

The term “dosing” refers to the administration of a substance (e.g., ananti-TNFα antibody) to achieve a therapeutic objective (e.g., treatmentof rheumatoid arthritis).

The term “dosing regimen” describes a treatment schedule for asubstance, such as a TNFα inhibitor, e.g., a treatment schedule over aprolonged period of time and/or throughout the course of treatment, e.g.administering a first dose of a TNFα inhibitor at week 0 followed by asecond dose of a TNFα inhibitor on a biweekly dosing regimen.

The term “biweekly dosing regimen”, “biweekly dosing”, and “biweeklyadministration” refer to the time course of administering a substance(e.g., an anti-TNFα antibody) to a patient to achieve a therapeuticobjective, e.g., throughout the course of treatment. The biweekly dosingregimen is not intended to include a weekly dosing regimen. Preferably,the substance is administered every 9 to 19 days, more preferably, every11 to 17 days, even more preferably, every 13 to 15 days, and mostpreferably, every 14 days. In one embodiment, the biweekly dosingregimen is initiated in a patient at week 0 of treatment. In anotherembodiment, a maintenance dose is administered on a biweekly dosingregimen. In one embodiment, both the loading and maintenance doses areadministered according to a biweekly dosing regimen. In one embodiment,biweekly dosing includes a dosing regimen wherein doses of a TNFαinhibitor are administered to a patient every other week beginning atweek 0. In one embodiment, biweekly dosing includes a dosing regimenwhere doses of a TNFα inhibitor are administered to a patient everyother week consecutively for a given time period, e.g., 4 weeks, 8weeks, 16, weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48weeks, 52 weeks, 56 weeks, etc. Biweekly dosing methods are alsodescribed in U.S. 2003/0235585.

The term “combination” as in the phrase “a first agent in combinationwith a second agent” includes co-administration of a first agent and asecond agent, which for example may be dissolved or intermixed in thesame pharmaceutically acceptable carrier, or administration of a firstagent, followed by the second agent, or administration of the secondagent, followed by the first agent.

The term “concomitant” as in the phrase “concomitant therapeutictreatment” includes administering an agent in the presence of a secondagent. A concomitant therapeutic treatment method includes methods inwhich the first, second, third, or additional substances areco-administered. A concomitant therapeutic treatment method alsoincludes methods in which the first or additional agents areadministered in the presence of a second substance or additionalsubstances, wherein the second or additional agents, for example, mayhave been previously administered. A concomitant therapeutic treatmentmethod may be executed step-wise by different patients. For example, onesubject may administer to a patient a first agent and a second subjectmay to administered to the patient a second substance, and theadministering steps may be executed at the same time, or nearly the sametime, or at distant times, so long as the first substance (andadditional substances) are after administration in the presence of thesecond substance (and additional substances). The actor and the patientmay be the same entity (e.g., human).

The term “combination therapy” refers to the administration of two ormore therapeutic substances, e.g., an anti-TNFα antibody and anotherdrug. The other drug(s) may be administered concomitant with, prior to,or following the administration of an anti-TNFα antibody.

The term “treatment” refers to therapeutic treatment, as well asprophylactic or suppressive measures, for the treatment of a disorder,such as a disorder in which TNFα is detrimental, e.g., rheumatoidarthritis.

The term “patient” or “user” refers to any type of animal, human ornon-human, that may be injected a substance using exemplary automaticinjection devices.

The terms “wearable automatic injection device” and “wearableautoinjector” refer to a device worn by a patient that enables thepatient to self-administer a therapeutically effective dose of atherapeutic agent by either fastening the wearable device directly tohis or her skin or fastening the wearable device to an article ofclothing that allows penetration of a hypodermic needle, wherein thewearable device differs from a conventional syringe by the inclusion ofa mechanism for automatically delivering the therapeutic agent to thepatient by injection when the mechanism is engaged.

The terms “syringe” and “cartridge” encompass a sterile barrel portionthat is filled with a dose of a therapeutic agent prior to distributionor sale to a patient or other non-medical professional foradministration of the therapeutic agent to a patient. In an exemplaryembodiment, a distal end of the barrel portion of a syringe may becoupled to a sterile hypodermic needle. In an exemplary embodiment, adistal end of the barrel portion of a cartridge may not be coupled to aneedle. That is, in exemplary embodiments, a syringe may be a cartridgewith a pre-attached hollow needle coupled to its barrel portion.

Exemplary embodiments described herein with reference to a syringeassembly may also be implemented using a cartridge assembly. Similarly,exemplary embodiments described herein with reference to a cartridgeassembly may also be implemented using a syringe assembly.

The term “vessel” refers to either a syringe or cartridge that may beused in an exemplary wearable automatic injection device for holding adose of a therapeutic agent.

The term “injection needle” refers to a needle in a wearable automaticinjection device that is inserted into a patient's body to deliver adose of a therapeutic agent into the patient's body. In an exemplaryembodiment, the injection needle may be directly coupled to or incontact with a syringe or a cartridge assembly that holds the dose ofthe therapeutic agent. In another exemplary embodiment, the injectionneedle may be indirectly coupled to the syringe or cartridge assembly,for example, via a syringe needle and/or a transfer mechanism thatprovides fluid communication between the syringe or cartridge and theinjection needle.

The term “syringe needle” refers to a needle in a wearable automaticinjection device that is coupled to or in contact with a syringe or acartridge assembly for conveying a dose of a therapeutic agent from thesyringe or cartridge assembly to an injection needle which, in turn,delivers the therapeutic agent into a patient's body. In an exemplaryembodiment, the syringe needle is not inserted into the patient's body.In another exemplary embodiment, the syringe needle may be inserted intothe patient's body.

In an exemplary wearable automatic injection device including a syringeassembly, the syringe needle may be coupled directly to the barrelportion of the syringe and may be in fluid communication with the barrelportion. In an exemplary wearable automatic injection device including acartridge assembly, the syringe needle may be provided separately fromthe barrel portion of the cartridge, for example, within an injectionbutton or a transfer mechanism. During an injection stage, the syringeneedle may be inserted into a distal end of the barrel portion of thecartridge to establish fluid communication between the syringe needleand the barrel portion.

The term “pre-injection state” refers to a state of a wearable automaticinjection device prior to the start of delivery of a therapeutic agentcontained in the device.

The term “injection state” refers to one or more states of a wearableautomatic injection device during the delivery of a therapeutic agentcontained in the device.

The term “post-injection state” refers to completion of delivery of atherapeutically effective dose of a therapeutic agent contained in thedevice and to removal of the device from the patient prior to completionof delivery of a therapeutically effective dose of the therapeuticagent.

The term “slow” refers to a delivery rate of a volume of a therapeuticagent. In an exemplary embodiment, a volume of about 0.1 milliliters toabout 1 milliliter or more may be delivered in a delivery time period ofabout ten seconds to about twelve hours. In a preferred embodiment, thedelivery time period may range from about five minutes to about thirtyminutes.

The term “clothing” refers to any suitable covering on a patient's bodyto which an exemplary wearable automatic injection device may be coupledor attached. The article of clothing may thus form an intermediate layerbetween the device and the patient's skin and may be used to indirectlycouple the device to the patient's skin. In an exemplary embodiment, thearticle of clothing may be snug clothing on the patient's body, forexample, nylon stockings. In another exemplary embodiment, the articleof clothing may be a covering on the patient's skin including, but notlimited to, a medical tape, a bandage, and the like. In anotherexemplary embodiment, the article of clothing may be a couplingmechanism that adheres the device in the proximity of the patient's skinincluding, but not limited to, a sleeve that may fit round a portion ofthe patient's body, a belt, a strap (e.g., a Velcro strap), and thelike.

II. EXEMPLARY EMBODIMENTS

Certain exemplary wearable automatic injection devices are describedwith reference to FIGS. 1-10. Certain exemplary needle systems that maybe used in exemplary wearable automatic injection devices to convey atherapeutic agent are described with reference to FIGS. 11-23. Certainexemplary plunger actuation systems that may be used in exemplarywearable automatic injection devices to expel a therapeutic agent from asyringe or cartridge are described with reference to FIGS. 24-51.Certain exemplary needle protection systems that may be used inexemplary wearable automatic injection devices to maintain an injectionneedle in a retracted position in a post-injection state are describedwith reference to FIGS. 52-55.

Exemplary wearable automatic injection devices may employ a syringeassembly (as illustrated in FIGS. 1A-1F) or a cartridge assembly (asillustrated in FIGS. 2A-2F) for holding a dose of a therapeutic agentthat may be delivered into a patient's body through an injection needle.

FIGS. 1A-1F illustrate an exemplary embodiment of a wearable automaticinjection device 100 including a syringe assembly that may be used toinject a dose of a therapeutic agent into the body of a patient. FIG. 1Aillustrates a first end view and a first side view of the exemplarywearable device 100 in a packaged pre-injection state. FIG. 1Billustrates the first end view and the first side view of the exemplarydevice 100 in a pre-injection state in which a needle shield coveringthe injection needle is removed in preparation for an injection. FIG. 1Cillustrates the first end view and the first side view of the exemplarydevice 100 during an injection in an injection state in which thepatient's skin is pierced by the injection needle. FIG. 1D illustratesthe first end view and the first side view of the exemplary device 100during an injection in an injection state in which the barrel portioncontaining the dose of the therapeutic agent is deployed forwardlywithin the housing of the device 100. FIG. 1E illustrates the first endview and the first side view of the exemplary device 100 during aninjection in an injection state in which the bung is actuated by aplunger actuator to expel the dose of the therapeutic agent from thebarrel portion. FIG. 1F illustrates the first end view and the firstside view of the exemplary device 100 after an injection in apost-injection state in which the injection needle is retracted withinthe housing of the device 100.

The wearable automatic injection device 100 may include a housing 102.In an exemplary embodiment, the housing 102 may have an elongatedconfiguration, although one of ordinary skill in the art will recognizethat the housing 102 may have any suitable size, shape and configurationfor housing a barrel portion containing a dose of a therapeutic agent tobe injected. In an exemplary embodiment, the housing 102 may be formedof any suitable material including, but not limited to, plastic andother known materials.

The housing 102 of the wearable automatic injection device 100 mayinclude an adhesive layer 124 disposed along a patient contact portionat the bottom of the housing 102 that is placed proximal to the skin ofthe patient or an article of clothing of the patient. In some exemplaryembodiments, the adhesive layer 124 may be configured to be placed onthe skin of the patient in order to attach the housing 102 to thepatient to deliver the dose of the therapeutic agent. The adhesive layer124 may include a non-adhesive tab 126 that is not adhesive. Thenon-adhesive tab 126 may be gripped by the patient and pulled to removethe wearable automatic injection device 100 from the skin or clothing ofthe patient.

Before the wearable automatic injection device 100 is put to use, e.g.,in the package state illustrated in FIG. 1A, the adhesive layer 124 maybe covered by a protective film 128 which preserves the adhesive natureof the adhesive layer 124. The protective film 128 may include a tab 130which may be gripped by the patient and pulled to remove the protectivefilm 128 from the adhesive layer 124. This exposes the adhesive layer124, allowing the patient to attach the housing 102 to his or her skinor article of clothing by placing the side with the adhesive layer 124on the skin or the article of clothing.

The housing 102 may house a syringe assembly extending substantiallyalong a longitudinal axis L between a proximal end (farthest from theinjection needle) and a distal end (nearest to the injection needle).The syringe assembly may include a barrel portion 106 for holding a dose108 of a therapeutic agent to be injected into a patient's skin. Thebarrel portion 106 may extend substantially along the longitudinal axisbetween a proximal end (farthest from the injection needle) and a distalend (nearest to the injection needle). In an exemplary embodiment, thebarrel portion 106 may be a substantially cylindrical member having acircular cross-section, although one of ordinary skill in the art willrecognize that the barrel portion 106 may have any suitable shape orconfiguration.

In an exemplary embodiment, the barrel portion 106 may be stationarywithin the housing 102 so that the injection process does not result inthe movement of the barrel portion 106 within and relative to thehousing 102. In another exemplary embodiment, the barrel portion 106 mayinitially, i.e., before an injection in a pre-injection state, be in aretracted position toward the proximal end of the device 100 (asillustrated in FIGS. 1A-1C), and may be actuated during an injection inan injection state to an extended position toward the distal end of thedevice 100.

A bung 110 may be provided at the proximal end of the barrel portion 106to seal the dose of the therapeutic agent within the barrel portion 106and to apply a force to the dose to expel the dose from the barrelportion 106. The bung 110 may be moveable within the barrel portion 106toward the distal end of the barrel portion 106 in order to expel thedose from the barrel portion 106 during an injection in an injectionstate. In an exemplary embodiment, the bung 110 may be configured toperform both functions of sealing the dose and squeezing the dose out ofthe barrel portion 106. In another exemplary embodiment, a bung may beprovided to seal the dose within the barrel portion 106 and a separatepiston or plunger rod may be provided to impart a force to the bung inorder to squeeze the dose out of the barrel portion 106.

The syringe assembly may include, at or near its distal end, a syringestopper or a distal portion of the syringe 114 that may include asyringe needle 120 and a needle cover 134 for covering the syringeneedle 120. The needle cover 134 may include a soft needle shield, arigid needle shield, or both. In an exemplary embodiment, the syringeneedle 120 may be aligned parallel to the longitudinal axis L of thedevice 100. The syringe needle 120 may have any suitable size, shape andconfiguration suitable for piercing a septum, and is not limited to theillustrative embodiment.

The syringe assembly may include, at or near its proximal end, a plungeractuator 112 for selectively actuating the bung 110 forwardly within thebarrel portion 106 toward the distal end in order to inject thetherapeutically effective dose contained in the barrel portion 106 intoa patient's skin. The plunger actuator 112 may employ an energy storageand controlled energy release mechanism to actuate the bung 110. Inexemplary embodiments, the plunger actuator 112 may be located outsidethe barrel portion 106 or partly or fully within the barrel portion 106.In an exemplary embodiments, the plunger actuator 112 may drive the bung110 directly or indirectly though the use of a plunger disposed betweenthe bung 110 and the plunger actuator 112.

In an exemplary embodiment, the plunger actuator 112 may include abiasing mechanism, e.g., a spring, that is retracted before injectionand that is released during injection to actuate the bung 110 forwardlywithin the barrel portion 106. In another exemplary embodiment, theplunger actuator 112 may include a chemical gas generator, e.g., anexpanding foam, that is in a non-expanded phase before injection andthat expands during injection to actuate the bung 110 forwardly withinthe barrel portion 106. In other exemplary embodiments, the plungeractuator 112 may employ hydraulic pressure of working fluids, gaspressure of compressed gases, osmotic pressure, hydrogel expansion, andthe like.

In an exemplary embodiment, the plunger actuator 112 may be movedforwardly within the barrel portion 106 in a substantially linearmanner, i.e., substantially constant speed. This may allow the dose tobe delivered to the patient at a substantially constant delivery rate.The plunger actuator 112 may include or may be coupled to a dampingmechanism that may be used to absorb energy, for example, an initialrelease of energy, and to provide a more controlled release of energyduring energy release by the plunger actuator 112. The controlledrelease of energy may result in a substantially linear delivery profile,i.e., a substantially constant rate of delivery of the dose over time,and may prevent abrupt changes in the speed of the delivery. In anexemplary embodiment, a plunger actuator 112 may employ the hydraulicpressure of a working fluid and a damping mechanism may employ a flowrestrictor placed in a fluid pathway between the working fluid and thebung 110. In another exemplary embodiment, a plunger actuator 112 mayemploy a biasing mechanism and a damping mechanism may employ a viscousdamper, a swiss lever escapement, a runaway escapement, and the like. Inanother exemplary embodiment, a plunger actuator 112 may employ astepper motor connected to a gear drive system to provide a constantlinear delivery profile.

The housing 102 of the wearable automatic injection device 100 may alsohouse an injection button 116 bearing a hollow hypodermic injectionneedle 118 that is configured to pierce the patient's skin. In anexemplary embodiment, the injection needle 118 may be alignedorthogonally to the longitudinal axis L of the device 100. In anexemplary embodiment, the injection needle 118 may be held in place byan injection needle carrier (not pictured) provided in the injectionbutton 116 or separately from the injection button 116. The injectionneedle 118 may have any suitable size, shape and configuration suitablefor piercing the skin of the patient to deliver the therapeutic agent,and is not limited to the illustrative embodiment. Suitable needles mayhave a length configured or selected to provide an injection depthsuitable for the desired therapy. Subcutaneous injections typicallypenetrate about six to ten millimeters into the skin. In an exemplaryembodiment, the injection needle 118 may have a length of about twelvemm and may be injected to a depth of about seven mm into the skin. Inother exemplary embodiments, the injection needle 118 may have lengthssuitable for intradermal, other subcutaneous, or intramusculartherapies. Suitable injection needles may have a wall thickness suitableto provide sufficient mechanism strength, a diameter suitable to allow adesired flow rate of the injected substance while minimizing patientsensation, and a tip geometry suitable for the desired therapy whileminimizing patient sensation. Suitable injection needles may be coatedas needed to minimize patient sensation as allowed by therapy. Theinjection needle 118 may be covered and maintained in aseptic condition,i.e., sterile condition, by a needle cover 122, for example, a rigidneedle shield, a soft needle shield, or both.

The injection button 116 may also include a pierceable septum disposedin the vicinity of the syringe needle 120. In a pre-injection state, thesyringe needle 120 does not pierce the septum, thus prevent fluidcommunication between the barrel portion 106 and the syringe needle 120.In an injection state, when pierced by a needle, for example, thesyringe needle 120, the septum may allow the dose to leave the barrelportion 106 and enter the syringe needle 120. In an exemplaryembodiment, one or more covers 115 may enclose the septum in a sterilitybarrier. The covers 115 may be pierced when the syringe needle 120pierces the septum.

In an exemplary embodiment, the injection needle 118 and the syringeneedle 120 may be coupled to and in fluid communication with each othervia the body of the injection button 116. In another exemplaryembodiment, the injection needle 118 and the syringe needle 120 may becoupled to and in fluid communication with each other via one or morefluid conduits (not pictured). In another exemplary embodiment, theinjection needle 118 and the syringe needle 120 may be directly coupledto and in fluid communication with each other.

In an exemplary embodiment, before an injection in a pre-injectionstate, the injection button 116 may be in a vertically raised positionrelative to the housing 102 such that the injection button 116 protrudesfrom the top of the housing 102, as illustrated in FIGS. 1A and 1B. Inthis position, the injection needle 118 may be retracted within thehousing 102 and may not be inserted into the patient's skin. In thisposition, the syringe needle 120 may be aligned vertically below theseptum in the syringe stopper 114 and may not pierce the septum. At thebeginning of the injection process, the injection button 116 may bepressed downward, for example, by a user of the device or automatically.This may push the injection button 116 to a vertically depressedposition relative to the housing 102 closer to the patient's skin suchthat the injection button 116 no longer protrudes from the top of thehousing 102, as illustrated in FIGS. 1C-1E. In this position, theinjection needle 118 may protrude from the bottom of the housing 102 andmay be inserted into the patient's skin. In this position, the syringeneedle 120 may be aligned with the septum in the syringe stopper 114 andmay pierce the septum.

In an exemplary embodiment, the septum may initially be spaced from theinjection button 116. In this embodiment, the syringe needle 120 maypierce the septum when the syringe stopper 114 bearing the syringeneedle 120 is advanced within the housing 102 toward the septum. Thatis, before an injection in a pre-injection state, the syringe needle 120may be spaced from the septum such that there is no fluid communicationbetween the barrel portion 106 and the injection needle 118 coupled tothe injection button 116. In an injection state, the barrel portion 106may advance within the housing 102 toward the distal end of the device100 such that that the syringe needle 120 may pierce the septum andestablish fluid communication between the barrel portion 106 and theinjection needle 118 coupled to the injection button 116. This fluidcommunication may allow the dose of the therapeutic agent to flow fromthe barrel portion 106 into the patient's skin through the syringeneedle 120 and the injection needle 118 when pressure is applied to thedose by the bung 110 during an injection in an injection state.

Referring now to FIG. 1F, in an exemplary embodiment, the housing 102 ofthe wearable automatic injection device 100 may include a skin sensorfoot 132, which is a structure housed under or in the portion of thehousing 102 proximal to the injection site. Prior to injection of thetherapeutic agent and during injection, the skin sensor foot 132 isretained within or forms a portion of the underside of the housing 102.When the wearable automatic injection device 100 is attached to theinjection site and activated, the skin sensor foot 132 may be free tomove but may be constrained by the injection site. When the wearableautomatic injection device 100 is removed from the injection site,regardless of whether the drug delivery was completed, the skin sensorfoot 132 is no longer constrained, and extends and projects outside theperiphery of the housing 102. This, in turn, trips a retraction trigger.When the retraction trigger is activated, a retraction mechanismretracts the injection needle 120 which may also raise the injectionbutton 116 from the vertically lowered position to the vertically raisedposition, so that the injection button 116 protrudes from the top of thehousing 102 and the injection needle 118 is retracted within the housing102.

FIG. 1A illustrates the wearable automatic injection device 100 in apre-injection state, for example, as packaged, in which the barrelportion 106 may be pre-fillable and/or pre-filled with the dose 108 ofthe therapeutic agent and in a retracted position ready for use. Thebarrel portion 106 may contain the dose 108 of the therapeutic agent inthe interior space defined between the wall or walls of the barrelportion 106 and the bung 110. In an embodiment, the plunger actuator 112may store energy that, when released, may actuate the bung 110. Theinjection button 116 may be partially disposed within the housing 102 atthe vertically raised position above the injection site, and theinjection needle 118 may be retracted within the housing 102. Theprotrusion of the injection button 116 out of the top of the housing 102may provide a visual indication to the patient that the wearableautomatic injection device 100 is not in operation.

FIG. 1B illustrates the wearable automatic injection device 100 in apre-injection state in which the needle cover 122 and the septum coverare removed. In exemplary embodiments, the protective film 128 mayinclude a linking member that is connected to the needle cover 122, theseptum and syringe needle covers in the syringe stopper 114. The linkingmember may include a tether or other linkage mechanism. When theprotective film 128 is removed, the linking member of the protectivefilm 128 may remove the needle cover 122 and the septum and syringeneedle covers in the syringe stopper 114.

FIG. 1C illustrates the wearable automatic injection device 100 duringan injection in an injection state in which the injection button 116 isin the vertically lowered position within the housing 102. In thevertically lowered position, the injection button 116 may be disposedwithin the housing 102 at a depressed or vertically lowered locationabove the injection site, and the injection needle 118 may project fromthe bottom of the housing 102 through an aperture in the housing 102 sothat it can penetrate the skin at the injection site. In the verticallylowered state, the injection button 116 may not protrude from the top ofthe housing 102, which may provide a visual indication to the patientthat the wearable automatic injection device 100 is in operation.

FIG. 1D illustrates the wearable automatic injection device 100 duringan injection in an injection state in which the barrel portion 106containing the dose 108 of the therapeutic agent is deployed forwardlyfrom a retracted position to an extended position within the housing ofthe device 100. The advancement of the barrel portion 106 may bring thedistal end of the barrel portion 106 or the syringe stopper 114 in thevicinity of or in contact with the injection button 116. In an exemplaryembodiment, the syringe needle 120 may pierce the septum held in thesyringe stopper 114 in order to establish fluid communication betweenthe barrel portion 106 and the injection needle 118.

FIG. 1E illustrates the wearable automatic injection device 100 duringan injection in an injection state in which the plunger actuator 112 istriggered to move the bung 110. Triggering of the plunger actuator 112may release stored energy in the plunger actuator 112 in order to movethe bung 110 within the barrel portion 106 toward the distal end of thedevice 100. The movement of the bung 110 may eject the dose of thetherapeutic agent from the barrel portion 106 through the distal end ofthe barrel portion 106. Any suitable mechanism may be used to triggerthe plunger actuator 112 including, but not limited to, a linking memberthat is coupled to and activated by the depression of the injectionbutton 116 or by the removal of the needle cover 122, a trigger buttonthat may be used by the user, and the like.

FIG. 1F illustrates the wearable automatic injection device 100 after aninjection in a post-injection state, for example, after injecting atherapeutically effective dose of the therapeutic agent or removal ofthe wearable automatic injection device 100 from the patient beforedelivery of a therapeutically effective dose of the therapeutic agent,in which the injection button 116 is in the vertically raised position.In the vertically raised position, the injection button 116 may bedisposed partly within the housing 102 at an elevated or verticallyraised location above the injection site, and the injection needle 118may be retracted within the housing 102. A portion of the injectionbutton 116 may project from the top of the housing 102 to provide avisual indication to the patient that the wearable automatic injectiondevice assembly 100 is not in operation (i.e., in a post-injectionstate). The barrel portion 106 may be empty of the therapeutic agent andthe plunger actuator 112 may no longer store energy. A skin sensor foot132 may extend from the bottom of the housing 102 upon removal of thedevice 100 from the injection site.

The housing 102 may include a retraction mechanism that automaticallyraises the injection button 116 from the vertically lowered injectionstate (shown in FIGS. 1C-1E) to the vertically raised post-injectionstate (shown in FIG. 1F). In an exemplary embodiment, the retractionmechanism may include a biasing mechanism, e.g., a spring, that biasesthe syringe assembly away from the injection site when the retractionmechanism is triggered.

A retraction trigger, when activated, may trigger the retractionmechanism in order to raise the injection button 116 from the verticallylowered state to the vertically raised state. In an exemplaryembodiment, the bung 110 and/or the plunger actuator 112 may include alinking member connected to the retraction trigger. The linking membermay include a tether or other linkage mechanism. The linking member maybe of a suitable length such that, when the bung 110 has been moved tothe end of the barrel portion 106 (delivering a complete dose), thelinking member triggers a latch that in turn trips the retractiontrigger. In another exemplary embodiment, the extension of the skinsensor foot 132 from the bottom of the housing 102 may trip theretraction trigger.

In an exemplary embodiment, the retraction mechanism may include anend-of-dose retraction trigger that, when tripped, triggers theretraction mechanism. The end-of-dose retraction trigger may be trippedwhen the therapeutically effective dose of therapeutic agent in thewearable automatic injection device is delivered. In an exemplaryembodiment, the end-of-dose retraction trigger may include a latch,e.g., a flexible plastic hook, that is released upon completed drugdelivery. The retraction mechanism may also include an early-removalretraction trigger that, when tripped, triggers the retractionmechanism. The early-removal retraction trigger may be tripped when thewearable automatic injection device is removed from the injection sitebefore the therapeutically effective dose of therapeutic agent iscompletely delivered. In an exemplary embodiment, the early-removalretraction trigger may include a latch, e.g., a flexible plastic hook,that is released upon removal of the wearable automatic injection device100 from the injection site. The retraction mechanism is responsive tothe end-of-dose retraction trigger and responsive to the early-removalretraction trigger to automatically retract the syringe assembly fromthe injection site.

In an exemplary embodiment, raising of the injection button 116 to thevertically raised position may cause the syringe needle 120 to bendupward, thus preventing undesirable reuse of the syringe needle and thewearable automatic injection device.

FIGS. 2A-2F illustrate an exemplary embodiment of a wearable automaticinjection device 200 including a cartridge assembly that may be used toinject a dose of a therapeutic agent into the body of a patient. FIG. 2Aillustrates a first end view and a first side view of the exemplarywearable device 200 in a packaged pre-injection state. FIG. 2Billustrates the first end view and the first side view of the exemplarydevice 200 in a pre-injection state in which a needle shield coveringthe injection needle is removed in preparation for an injection. FIG. 2Cillustrates the first end view and the first side view of the exemplarydevice 200 during an injection in an injection state in which thepatient's skin is pierced by the injection needle. FIG. 2D illustratesthe first end view and the first side view of the exemplary device 200during an injection in an injection state in which the barrel portioncontaining the dose of the therapeutic agent is deployed forwardlywithin the housing of the device 200. FIG. 2E illustrates the first endview and the first side view of the exemplary device 200 during aninjection in an injection state in which the bung is actuated by aplunger actuator to expel the dose of the therapeutic agent from thebarrel portion. FIG. 2F illustrates the first end view and the firstside view of the exemplary device 200 after an injection in apost-injection state in which the injection needle is retracted withinthe housing of the device 200.

The wearable automatic injection device 200 may include a housing 202.In an exemplary embodiment, the housing 202 may have an elongatedconfiguration, although one of ordinary skill in the art will recognizethat the housing 202 may have any suitable size, shape and configurationfor housing a barrel portion containing a dose of a therapeutic agent tobe injected. In an exemplary embodiment, the housing 202 may be formedof any suitable material including, but not limited to, plastic andother known materials.

The housing 202 of the wearable automatic injection device 200 mayinclude an adhesive layer 224 disposed along a patient contact portionat the bottom of the housing 202 that is placed proximal to the skin ofthe patient or an article of clothing of the patient. In some exemplaryembodiments, the adhesive layer 224 may be configured to be placed onthe skin of the patient in order to attach the housing 202 to thepatient to deliver the dose of the therapeutic agent. The adhesive layer224 may include a non-adhesive tab 226 that is not adhesive. Thenon-adhesive tab 226 may be gripped by the patient and pulled to removethe wearable automatic injection device 200 from the skin or clothing ofthe patient.

Before the wearable automatic injection device 200 is put to use, e.g.,in the package state illustrated in FIG. 2A, the adhesive layer 224 maybe covered by a protective film 228 which preserves the adhesive natureof the adhesive layer 124. The protective film 228 may include a tab 230which may be gripped by the patient and pulled to remove the protectivefilm 228 from the adhesive layer 224. This exposes the adhesive layer224, allowing the patient to attach the housing 202 to his or her skinor article of clothing by placing the side with the adhesive layer 224on the skin or the article of clothing.

The housing 202 may house a therapeutic agent cartridge assemblyextending substantially along a longitudinal axis L between a proximalend (farthest from the injection needle) and a distal end (nearest tothe injection needle). The cartridge assembly may include a barrelportion 206 for holding a dose 208 of a therapeutic agent to be injectedinto a patient's skin. The barrel portion 206 may extend substantiallyalong the longitudinal axis between a proximal end (farthest from theinjection needle) and a distal end (nearest to the injection needle). Inan exemplary embodiment, the barrel portion 206 may be a substantiallycylindrical member having a circular cross-section, although one ofordinary skill in the art will recognize that the barrel portion 206 mayhave any suitable shape or configuration.

In an exemplary embodiment, the barrel portion 206 may be stationarywithin the housing 202 so that the injection process does not result inthe movement of the barrel portion 206 within and relative to thehousing 202. In another exemplary embodiment, the barrel portion 206 mayinitially, i.e., before an injection in a pre-injection state, be in aretracted position toward the proximal end of the device 200 (asillustrated in FIGS. 2A-2C), and may be actuated during an injection inan injection state to an extended position toward the distal end of thedevice 200.

A bung 210 may be provided at the proximal end of the barrel portion 206to seal the dose of the therapeutic agent within the barrel portion 206and to apply a force to the dose to expel the dose from the barrelportion 206. The bung 210 may be moveable within the barrel portion 206toward the distal end of the barrel portion 206 in order to expel thedose from the barrel portion 206 during an injection in an injectionstate. In an exemplary embodiment, the bung 210 may be configured toperform both functions of sealing the dose and squeezing the dose out ofthe barrel portion 206. In another exemplary embodiment, a bung may beprovided to seal the dose within the barrel portion 206 and a separatepiston may be provided to impart a force to the bung in order to squeezethe dose out of the barrel portion 206.

The cartridge assembly may include, at or near its proximal end, aplunger actuator 212 for selectively actuating the bung 210 forwardlywithin the barrel portion 206 toward the distal end in order to injectthe therapeutically effective dose contained in the barrel portion 206into a patient's skin. The plunger actuator 212 may employ an energystorage and controlled energy release mechanism to actuate the bung 210.In exemplary embodiments, the plunger actuator 212 may be locatedoutside the barrel portion 206 or partly or fully within the barrelportion 206. In an exemplary embodiment, the plunger actuator 212 maydrive the bung 210 directly or indirectly though the use of a plungerdisposed between the bung 210 and the plunger actuator 212.

In an exemplary embodiment, the plunger actuator 212 may include abiasing mechanism, e.g., a spring, that is retracted before injectionand that is released during injection to actuate the bung 210 forwardlywithin the barrel portion 206. In another exemplary embodiment, theplunger actuator 212 may include a chemical gas generator, e.g., anexpanding foam, that is in a non-expanded phase before injection andthat expands during injection to actuate the bung 210 forwardly withinthe barrel portion 206. In other exemplary embodiments, the plungeractuator 212 may employ hydraulic pressure of working fluids, gaspressure of compressed gases, osmotic pressure, hydrogel expansion, andthe like.

In an exemplary embodiment, the plunger actuator 212 may be movedforwardly within the barrel portion 206 in a substantially linearmanner, i.e., substantially constant speed. This may allow the dose tobe delivered to the patient at a substantially constant delivery rate.The plunger actuator 212 may include or may be coupled to a dampingmechanism that may be used to absorb energy, for example, an initialrelease of energy, and to provide a more controlled release of energyduring energy release by the plunger actuator 212. The controlledrelease of energy may result in a substantially linear delivery profile,i.e., a substantially constant rate of delivery of the dose over time,and may prevent abrupt changes in the speed of the delivery.

In an exemplary embodiment, a plunger actuator 212 may employ one ormore fluid circuits containing a working fluid in which the hydraulicpressure of the working fluid applies a force to the bung to move thebung within the barrel portion of the cartridge. A damping mechanism mayemploy a flow restrictor placed in the fluid circuit between a source ofthe working fluid and the bung.

In another exemplary embodiment, a plunger actuator 212 may employ abiasing mechanism, for example, a spiral spring or a helical compressionspring. A damping mechanism may employ a viscous damper, a swiss leverescapement, a runaway escapement, and the like.

In another exemplary embodiment, a plunger actuator 212 may employ astepper motor connected to a gear drive system to provide a constantlinear delivery profile.

The cartridge assembly may include, at or near its distal end, acartridge stopper 214 that may include a septum and a cover 215 for theseptum. The septum may be a pierceable layer of material that isdisposed adjacent to the distal end of the barrel portion 206 in orderto seal the dose in the barrel portion 206. When intact, the septum mayseal the dose within the barrel portion 206. When pierced by a needle,for example, a syringe needle, the septum may allow the dose to leavethe barrel portion 206 and enter the syringe needle. The septum may beformed of a material that may be pierced by a syringe needle. A covermay be provided to protectively cover the septum from accidentalpiercing by the syringe needle when the device 200 is in the packagedpre-injection state as illustrated in FIG. 2A. In an exemplaryembodiment, the cartridge stopper 214 may also include a cover toprotectively cover a syringe needle provided in the vicinity of thecartridge stopper 214, thereby preventing accidental piercing of theseptum by the syringe needle when the device 200 is in the packagedpre-injection state as illustrated in FIG. 2A.

The housing 202 of the wearable automatic injection device 200 may alsohouse an injection button 216 bearing a hollow hypodermic injectionneedle 218 that is configured to pierce the patient's skin. In anexemplary embodiment, the injection needle 218 may be alignedorthogonally to the longitudinal axis L of the device 200. In anexemplary embodiment, the injection needle 218 may be held in place byan injection needle carrier (not pictured) provided in the injectionbutton 216 or separately from the injection button 216. The injectionneedle 218 may have any suitable size, shape and configuration suitablefor piercing the skin of the patient to deliver the therapeutic agent,and is not limited to the illustrative embodiment. Suitable needles mayhave a length configured or selected to provide an injection depthsuitable for the desired therapy. Subcutaneous injections typicallypenetrate about six to ten millimeters into the skin. In an exemplaryembodiment, the injection needle 218 may have a length of about twelvemm and may be injected to a depth of about seven mm into the skin. Inother exemplary embodiments, the injection needle 218 may have lengthssuitable for intradermal, other subcutaneous, or intramusculartherapies. Suitable injection needles may have a wall thickness suitableto provide sufficient mechanism strength, a diameter suitable to allow adesired flow rate of the injected substance while minimizing patientsensation, and a tip geometry suitable for the desired therapy whileminimizing patient sensation. Suitable injection needles may be coatedas needed to minimize patient sensation as allowed by therapy. Theinjection needle 218 may be covered and maintained in a septic conditionby a needle cover 222, for example, a rigid needle shield, a soft needleshield, or both.

The injection button 216 may also bear a hollow syringe needle 220configured to pierce the septum and establish fluid communication withthe barrel portion 206. In an exemplary embodiment, the syringe needle220 may be aligned parallel to the longitudinal axis L of the device200. The syringe needle 220 may have any suitable size, shape andconfiguration suitable for piercing the septum and is not limited to theillustrative embodiment.

In an exemplary embodiment, the injection needle 218 and the syringeneedle 220 may be coupled to and in fluid communication with each othervia the body of the injection button 216. In another exemplaryembodiment, the injection needle 218 and the syringe needle 220 may becoupled to and in fluid communication with each other via one or morefluid conduits (not pictured). In another exemplary embodiment, theinjection needle 218 and the syringe needle 220 may be directly coupledto and in fluid communication with each other.

In an exemplary embodiment, before an injection in a pre-injectionstate, the injection button 216 may be in a vertically raised positionrelative to the housing 202 such that the injection button 216 protrudesfrom the top of the housing 202, as illustrated in FIGS. 2A and 2B. Inthis position, the injection needle 218 may be retracted within thehousing 202 and may not be inserted into the patient's skin. In thisposition, the syringe needle 220 may be aligned vertically above theseptum in the cartridge stopper 214 and may not pierce the septum. Atthe beginning of the injection process, the injection button 216 may bepressed downward, for example, by a user of the device or automatically.This may push the injection button 216 to a vertically depressedposition relative to the housing 202 closer to the patient's skin suchthat the injection button 216 no longer protrudes from the top of thehousing 202, as illustrated in FIGS. 2C-2E. In this position, theinjection needle 218 may protrude from the bottom of the housing 202 andmay be inserted into the patient's skin. In this position, the syringeneedle 220 may be aligned with the septum in the cartridge stopper 214and may pierce the septum.

In an exemplary embodiment, the septum may initially be spaced from theinjection button 216. In this embodiment, the syringe needle 220 maypierce the septum when the cartridge stopper 214 bearing the septum isadvanced within the housing 202 toward the injection button 216. Thatis, before an injection in a pre-injection state, the syringe needle 220may be spaced from the septum such that there is no fluid communicationbetween the barrel portion 206 and the injection needle 218 coupled tothe injection button 216. In an injection state, the barrel portion 206may advance within the housing 202 toward the distal end of the device200 so that the syringe needle 220 may pierce the septum and establishfluid communication between the barrel portion 206 and the injectionneedle 218 coupled to the injection button 216. This fluid communicationmay allow the dose of the therapeutic agent to flow from the barrelportion 206 into the patient's skin through the syringe needle 220 andthe injection needle 218 when pressure is applied to the dose by thebung 210 during an injection in an injection state.

Referring now to FIG. 2F, in an exemplary embodiment, the housing 202 ofthe wearable automatic injection device 200 may include a skin sensorfoot 232, which is a structure housed under or in the portion of thehousing 202 proximal to the injection site. Prior to injection of thetherapeutic agent and during injection, the skin sensor foot 232 isretained within or forms a portion of the underside of the housing 202.When the wearable automatic injection device 200 is attached to theinjection site and activated, the skin sensor foot 232 may be free tomove but may be constrained by the injection site. When the wearableautomatic injection device 200 is removed from the injection site,regardless of whether the drug delivery was completed, the skin sensorfoot 232 is no longer constrained, and extends and projects outside theperiphery of the housing 202. This, in turn, trips a retraction trigger.When the retraction trigger is activated, a retraction mechanismretracts the injection needle 220 which may also raise the injectionbutton 216 from the vertically lowered position to the vertically raisedposition, so that the injection button 216 protrudes from the top of thehousing 202 and the injection needle 218 is retracted within the housing202.

FIG. 2A illustrates the wearable automatic injection device 200 in apre-injection state, for example, as packaged, in which the barrelportion 206 may be pre-fillable and/or pre-filled with the dose 208 ofthe therapeutic agent and in a retracted position ready for use. Thebarrel portion 206 may contain the dose 208 of the therapeutic agent inthe interior space defined between the wall or walls of the barrelportion 206 and the bung 210. In an embodiment, the plunger actuator 212may store energy that, when released, may actuate the bung 210. Theinjection button 216 may be partially disposed within the housing 202 atthe vertically raised position above the injection site, and theinjection needle 218 may be retracted within the housing 202. Theprotrusion of the injection button 216 out of the top of the housing 202may provide a visual indication to the patient that the wearableautomatic injection device 200 is not in operation.

FIG. 2B illustrates the wearable automatic injection device 200 in apre-injection state in which the needle cover 222 and the septum coverare removed. In exemplary embodiments, the protective film 228 mayinclude a linking member that is connected to the needle cover 222 andthe septum and syringe needle covers in the cartridge stopper 214. Thelinking member may include a tether or other linkage mechanism. When theprotective film 228 is removed, the linking member of the protectivefilm 228 may remove the needle cover 222 and the septum and syringeneedle covers in the cartridge stopper 214.

FIG. 2C illustrates the wearable automatic injection device 200 duringan injection in an injection state in which the injection button 216 isin the vertically lowered position within the housing 202. In thevertically lowered position, the injection button 216 may be disposedwithin the housing 202 at a depressed or vertically lowered locationabove the injection site, and the injection needle 218 may project fromthe bottom of the housing 202 through an aperture in the housing 202 sothat it can penetrate the skin at the injection site. In the verticallylowered state, the injection button 216 may not protrude from the top ofthe housing 202, which may provide a visual indication to the patientthat the wearable automatic injection device 200 is in operation.

FIG. 2D illustrates the wearable automatic injection device 200 duringan injection in an injection state in which the barrel portion 206containing the dose 208 of the therapeutic agent is deployed forwardlyfrom a retracted position to an extended position within the housing ofthe device 200. The advancement of the barrel portion 206 may bring thedistal end of the barrel portion 206 or the cartridge stopper 214 in thevicinity of or in contact with the injection button 216. In an exemplaryembodiment, the syringe needle 220 may pierce the septum held in thecartridge stopper 214 in order to establish fluid communication betweenthe barrel portion 206 and the injection needle 218.

FIG. 2E illustrates the wearable automatic injection device 200 duringan injection in an injection state in which the plunger actuator 212 istriggered to move the bung 210. Triggering of the plunger actuator 212may release stored energy in the plunger actuator 212 in order to movethe bung 210 within the barrel portion 206 toward the distal end of thedevice 200. The movement of the bung 210 may eject the dose of thetherapeutic agent from the barrel portion 206 through the distal end ofthe barrel portion 206. Any suitable mechanism may be used to triggerthe plunger actuator 212 including, but not limited to, a linking memberthat is coupled to and activated by the depression of the injectionbutton 216 or by the removal of the needle cover 222, a trigger buttonthat may be used by the user, and the like.

FIG. 2F illustrates the wearable automatic injection device 200 after aninjection in a post-injection state, for example, after injecting atherapeutically effective dose of the therapeutic agent or removal ofthe wearable automatic injection device 200 from the patient beforedelivery of a therapeutically effective dose of the therapeutic agent,in which the injection button 216 is in the vertically raised position.In the vertically raised position, the injection button 216 may bedisposed partly within the housing 202 at an elevated or verticallyraised location above the injection site, and the injection needle 218may be retracted within the housing 202. A portion of the injectionbutton 216 may project from the top of the housing 202 to provide avisual indication to the patient that the wearable automatic injectiondevice assembly 200 is not in operation (i.e., in a post-injectionstate). The barrel portion 206 may be empty of the therapeutic agent andthe plunger actuator 212 may no longer store energy. A skin sensor foot232 may extend from the bottom of the housing 202 upon removal of thedevice 200 from the injection site.

The housing 202 may include a retraction mechanism that automaticallyraises the injection button 216 from the vertically lowered injectionstate (shown in FIGS. 2C-2E) to the vertically raised post-injectionstate (shown in FIG. 2F). In an exemplary embodiment, the retractionmechanism may include a biasing mechanism, e.g., a spring, that biasesthe cartridge assembly away from the injection site when the retractionmechanism is triggered.

A retraction trigger, when activated, may trigger the retractionmechanism in order to raise the injection button 216 from the verticallylowered state to the vertically raised state. In an exemplaryembodiment, the bung 210 and/or the plunger actuator 212 may include alinking member connected to the retraction trigger. The linking membermay include a tether or other linkage mechanism. The linking member maybe of a suitable length such that, when the bung 210 has been moved tothe end of the barrel portion 206 (delivering a complete dose), thelinking member triggers a latch that in turn trips the retractiontrigger. In another exemplary embodiment, the extension of the skinsensor foot 232 from the bottom of the housing 202 may trip theretraction trigger.

In an exemplary embodiment, the retraction mechanism may include anend-of-dose retraction trigger that, when tripped, triggers theretraction mechanism. The end-of-dose retraction trigger may be trippedwhen the therapeutically effective dose of therapeutic agent in thewearable automatic injection device is delivered. In an exemplaryembodiment, the end-of-dose retraction trigger may include a latch,e.g., a flexible plastic hook, that is released upon completed drugdelivery. The retraction mechanism may also include an early-removalretraction trigger that, when tripped, triggers the retractionmechanism. The early-removal retraction trigger may be tripped when thewearable automatic injection device is removed from the injection sitebefore the therapeutically effective dose of therapeutic agent iscompletely delivered. In an exemplary embodiment, the early-removalretraction trigger may include a latch, e.g., a flexible plastic hook,that is released upon removal of the wearable automatic injection device200 from the injection site. The retraction mechanism is responsive tothe end-of-dose retraction trigger and responsive to the early-removalretraction trigger to automatically retract the cartridge assembly fromthe injection site.

In exemplary embodiments, the barrel portion of the wearable automaticinjection device 100 (in FIG. 1)/200 (in FIG. 2) may be pre-fillableand/or pre-filled with any volume of a therapeutic agent, e.g., atherapeutic antibody, desired for intradermal, subcutaneous, orintramuscular injections. In an exemplary embodiment, the barrel portion106 may be pre-fillable and/or pre-filled with a volume of between about0.1 milliliters and about 1.0 milliliters, although exemplary devicesare not limited to this exemplary range of therapeutic agent volumes.

In exemplary embodiments, the wearable automatic injection device 100(in FIG. 1)/200 (in FIG. 2) may be used to inject a therapeuticallyeffective amount of therapeutic agent over a period of time ranging fromabout ten seconds to about twelve hours. Certain other exemplaryembodiments provide actuation devices and systems that cause actuationof the syringe plunger at a slow rate in order to deliver thetherapeutic agent to a patient at a slow rate. Exemplary slowembodiments may deliver therapeutic agent volumes of about 0.1milliliters to about 1 milliliter or more in about five minutes to aboutthirty minutes, although exemplary delivery rates are not limited tothis exemplary range.

Exemplary embodiments may provide a linear delivery profile for thetherapeutic agent so that the delivery rate is substantially constantover time. In some cases, a linear delivery profile may reducediscomfort experienced by the patient. In an exemplary embodiment, thetherapeutic agent may be delivered in a single slow bolus.

The rate of delivery of the therapeutic agent may be dependent on theambient temperature. At room temperature, i.e., about 72° F., theaccuracy of the delivery time may range between about three percent andabout ten percent.

Exemplary dimensions of exemplary devices are described with referenceto Tables 1-6. However, one of ordinary skill in the art will recognizethat the exemplary dimensions are provided for illustrative purposes,and that exemplary automatic injection devices are not limited to theillustrative dimensions.

In an exemplary embodiment, a wearable automatic injection device mayhave an exemplary length of about 4.37 inches, an exemplary width ofabout 2.12 inches, and an exemplary height of about 1.25 inches. In anexemplary embodiment, the diameter of the barrel portion is about 1.470inches and the length of the barrel portion is about 2.520 inches.Tables 1-3 summarize the components of the length, width and height,respectively, for two exemplary types of the exemplary device.

TABLE 1 Summary of components of the length of an exemplary device(inch) Element Type 1 Type 2 Wall thickness 0.185 0.120 Septum 0.3970.272 Needle 0.500 0.500 Barrel portion 2.520 2.520 Advance spring 0.4700.322 Hydraulic connection 0.113 0.113 Wall thickness 0.185 0.120 Total4.370 3.968

TABLE 2 Summary of components of the width of an exemplary device (inch)Element Type 1 Type 2 Wall thickness 0.185 0.120 Needle lock 1.045 0.935Barrel portion width 0.470 0.470 Syringe lock 0.235 0.235 Wall thickness0.185 0.120 Total 2.120 1.880

TABLE 3 Summary of components of the height of an exemplary device(inch) Element Type 1 Type 2 Wall thickness 0.100 0.120 Needle cover0.431 0.431 Septum 0.400 0.350 Spring solid height 0.200 0.000 Wallthickness 0.185 0.125 Total 1.316 1.026

In an exemplary embodiment, the diameter of the barrel portion inproduction may be increased from about 1.470 inches by about 0.125inches, and the length of the barrel portion may be decreased inproduction from about 2.520 inches by about 0.732 inches. Tables 4-6summarize the components of the length, width and height, respectively,for two exemplary types of the exemplary device.

TABLE 4 Summary of components of the length of an exemplary device(inch) Element Type 1 Type 2 Wall thickness 0.185 0.120 Septum 0.3970.272 Needle 0.500 0.250 Barrel portion 2.520 1.788 Advance spring 0.4700.322 Hydraulic connection 0.113 0.113 Wall thickness 0.185 0.120 Total4.370 2.986

TABLE 5 Summary of components of the width of an exemplary device (inch)Element Type 1 Type 2 Wall thickness 0.185 0..120 Needle lock 1.0450.935 Barrel portion width 0.470 0.595 Syringe lock 0.235 0.235 Wallthickness 0.185 0.120 Total 2.120 2.005

TABLE 6 Summary of components of the height of an exemplary device(inch) Element Type 1 Type 2 Wall thickness 0.100 0.120 Needle cover0.431 0.493 Septum 0.400 0.350 Spring solid height 0.200 0.000 Wallthickness 0.185 0.125 Total 1.316 1.088

FIG. 3 is a flow chart of an exemplary method 300 of assembling anexemplary automatic injection device 100. In step 302, a syringe or acartridge assembly may be sterilized and assembled. In step 304, aninjection button may be sterilized and assembled. In step 306, thebarrel portion of the syringe or cartridge assembly may be filled with adose of a therapeutic agent that is to be administered to a patient. Instep 308, a sterile bung may be placed in the barrel portion of thesyringe or cartridge assembly to seal the therapeutic agent inside thebarrel portion. The containment of the therapeutic agent inside thewearable automatic injection device by the sterile barrel portion andthe sterile bung maintains sterility of the therapeutic agent. As such,in an exemplary embodiment, the remaining components of the wearableautomatic injection device may be assembled in a non-sterile environmentafter the barrel portion is pre-fillable and/or pre-filled with thetherapeutic agent. For example, in step 310, a non-sterile plungeractuator, for example, a biasing mechanism may be inserted behind thebung.

In step 312, the syringe or cartridge assembly may be inserted into anon-sterile housing. The housing may be pre-assembled with othernon-sterile components, e.g., an adhesive layer, a protective film, askin sensor foot, and the like. In step 314, the injection button (withan enclosed sterile fluid path and one or more needles) may be insertedinto the non-sterile housing. In exemplary embodiments, the barrelportion, the enclosed hypodermic injection needle, the syringe needle,the needle cover, and the bung may provide the sterility barrier for thetherapeutic agent and the fluid path. Thus, once the barrel portion isfilled with the therapeutic agent and the bung is inserted into thebarrel portion, assembly of the remaining portions of the device doesnot require aseptic conditions. No therapeutic agent transfer steps needto be performed by the user. In step 316, the assembled automaticinjection device may be placed in an over-wrap, if necessary, and maythen be commercially packaged for sale. FIG. 1A illustrates an exemplaryembodiment of the assembled automatic injection device in the packagedpre-injection state.

FIG. 4 is a flow chart of an exemplary method 400 of using an exemplaryautomatic injection device. The wearable automatic injection devicepackaged and pre-fillable and/or pre-filled with a therapeutic agent maybe generally stored in refrigerated storage before use. In step 402, thepackaged automatic injection device may be removed from storage. In step404, the wearable automatic injection device may be removed from itspackaging and any over-wrap, and warmed to room temperature, e.g., byleaving the wearable device outside the packaging at room temperature orby warming the wearable device. In step 406, the patient may confirmthat the barrel portion contains a volume of the therapeutic agentthrough an therapeutic agent inspection window disposed in the devicehousing, and may also confirm the clarity of the therapeutic agent ifnecessary.

In step 408, the injection site on the skin of the patient may beselected and prepared for the delivery of the therapeutic agent. In step410, the patient uses the wearable automatic injection device to injectthe therapeutic agent into the injection site. The steps generallyinvolved within step 410 are described below in connection with FIG. 5.In step 412, after performing the injection, the wearable automaticinjection device may be removed from the patient and discarded in anappropriate manner.

FIG. 5 is a flow chart of an exemplary method 500 of using an exemplaryautomatic injection device to inject a therapeutically effective amountof a therapeutic agent into a patient. Exemplary method 500 is adetailed outline of step 410 in FIG. 4. In step 502, the patient removesthe protective film that covers and protects the adhesive layer of thewearable automatic injection device. In some exemplary embodiments,removal of the protective film also removes the needle cover and theseptum cover in the syringe or cartridge stopper.

In step 504, the patient applies the patient contact portion of thewearable automatic injection device with the adhesive layer to theinjection site (or an article of clothing around the injections site) sothat the device is reliably retained on the injection site during theinjection of the therapeutically effective dose of therapeutic agent.

In step 506, once the wearable automatic injection device is attached tothe injection site, the patient may depress the injection button from avertically raised position in the pre-injection state to a verticallylowered position in the injection state within the housing. In thevertically raised position, the end of the injection button bearing theinjection needle is retracted within the housing and is not exposed tothe outside of the housing. When depressed, the end of the injectionbutton bearing the injection needle is moved downward either linearly orrotationally within the housing so that the injection needle emergesfrom an aperture in the housing and is exposed. This allows theinjection needle to penetrate the skin of the patient to an appropriatedepth for injection of the therapeutic agent. The downward movement ofthe injection button in the housing may be linear (i.e., a verticaldownward movement) or rotary (i.e., in a circular movement about a pivotpoint).

In an exemplary embodiment, the injection button is depressed into thehousing by the patient manually pushing down the injection button. Inanother exemplary embodiment, the patient may activate an injectiontrigger, e.g., a trigger button located in a conveniently accessiblelocation such as the top of the housing, which causes the injectiontrigger to automatically depress the injection button into the housingand in turn, cause the injection needle to pierce the skin of thepatient. In an exemplary embodiment, pressing the injection triggerbutton may release a latch in the injection trigger that allows a springto bias the injection button downwardly in the housing. The same motionof the injection button may cause the injection needle to be insertedinto the injection site to an appropriate depth.

In step 508, depressing the injection button may trigger a syringe orcartridge actuator that moves the syringe or cartridge assembly, morespecifically, the barrel portion, forwardly within and relative to thehousing from a retracted position (in which the distal end of thesyringe or cartridge assembly is spaced from the injection button) to anextended position (in which the distal end of the syringe or cartridgeassembly is adjacent to and/or in contact with the injection button). Inanother exemplary embodiment, the syringe or cartridge actuator istriggered not by depressing the injection button, but by the useractivating a trigger, e.g., in the form of a trigger button. In anexemplary embodiment, movement of the syringe or cartridge assemblytoward the injection button may cause the syringe needle to pierce theseptum.

In step 510, when the distal end of the barrel portion makes contactwith the injection button, the plunger actuator may break the staticfriction (i.e., stiction) between the bung and the inside wall or wallsof the barrel portion and cause the bung to move forwardly toward thesyringe needle in the injection button to deliver the therapeutic agentvia the injection needle. The plunger actuator may overcome the bungstiction in one step and actuate the bung in a subsequent step, or theplunger actuator may overcome the bung stiction and actuate the bungconcurrently. Movement of the bung may cause the dose to be releasedthrough the syringe needle into the injection needle and thereby intothe patient's skin.

In an exemplary embodiment, the forward advancement of the syringe orcartridge assembly within the housing and the forward advancement of thebung within the barrel portion may take place in separate steps. Inanother exemplary embodiment, the forward advancement of the syringe orcartridge assembly within the housing and the forward advancement of thebung within the barrel portion may take place in the same step, forexample, simultaneously.

The rate of therapeutic agent delivery may depend on the characteristicsof the plunger actuator. The plunger actuator may take the form ofseveral exemplary embodiments. In some exemplary embodiments, theplunger actuator may employ means of energy storage and release, e.g.,biasing mechanisms (including, but not limited to, one or more springs,for example, spiral springs or helical compression springs), compressedgases, chemical gas generators (such as expanding foams), osmoticpressure, hydrogel expansion, etc. A damping or control mechanism(including, but not limited to, a viscous damper or an escapement) maybe used to absorb energy, for example, an initial release of energy, andto provide a more controlled release of energy during energy release bythe plunger actuator. A flow restrictor placed in a fluid pathwaybetween the needle and the bung may be used to further regulate the rateof therapeutic agent delivery, e.g., where the plunger actuator deliversan unconstrained spring force via a working fluid. Thus, an appropriateplunger actuator and an appropriate control mechanism may be selected todeliver the dose at a controlled rate, e.g., in a single slow bolus freeof or substantially free of any burning sensation to the patient.

In an exemplary embodiment, depressing the injection button may arm theretraction mechanism which, when triggered, retracts the injectionbutton into the housing 102 after an injection in a post-injectionstate.

In step 512, upon delivery of the therapeutically effective dose, thebung and/or the plunger actuator may trip the end-of-dose retractiontrigger of the retraction mechanism. The bung and/or the plungeractuator may include a linking member connected to the end-of-doseretraction trigger. The linking member may include a tether or otherlinkage mechanism. The linking member may be of a suitable length suchthat, when the bung has been moved to the end of the syringe orcartridge assembly (delivering a complete dose), the linking membertriggers a latch that in turn trips the retraction trigger.

In step 514, once the end-of-dose retraction trigger is tripped, theretraction mechanism may retract the injection button upward inside thehousing and away from the patient contact portion so that the syringe orcartridge assembly enters a post-injection state. In an exemplaryembodiment, the movement of the injection button from the injectionstate to the post-injection state creates an audible sound, e.g., a“click,” which provides an aural indication of the completion oftherapeutic agent delivery. Once retracted, the injection buttonprotrudes outside the housing, which provides a visual indication of thestate of the wearable automatic injection device, for example,completion of therapeutic agent delivery or a visual indication of thedevice in the post-injection state.

However, if the wearable device is removed from the skin of the patientbefore the completion of therapeutically effective dose of thetherapeutic agent, the skin sensor foot may extend to the outside of thehousing and trip the early-removal retraction trigger of the retractionmechanism. Once the early-removal retraction trigger is tripped, theretraction mechanism deploys the injection button upward in the housingaway from the patient contact portion so that the syringe or cartridgeassembly enters a post-injection state. In an exemplary embodiment, theplunger actuator may continue to move forwardly in the barrel portiontoward the syringe needle when the device is removed from the patientbefore completion of delivery of a therapeutically effective dose of thetherapeutic agent.

In step 516, upon retraction, a needle lock engages with the injectionneedle to prevent redeployment of the injection needle to provideneedle-stick protection. The needle lock may be a member that preventsthe injection needle from exiting the housing once engaged, and may belocated in the housing near the injection needle. Exemplary needle locksmay include, but are not limited to, a plastic plate, a metal plate, aclip, etc.

FIGS. 6A-6C illustrate an exemplary embodiment of a wearable automaticinjection device 600 suitable for linear insertion of a needle into theskin of a patient. By linear insertion, the end of a cartridge assemblybearing a needle descends linearly within a housing of the wearableautomatic injection device so that the needle is inserted into thepatient. More specifically, FIG. 6A illustrates the exemplary wearabledevice in a Pre-Injection State, for example, as packaged; FIG. 6Billustrates the exemplary wearable device in an Injection State justbefore, while or just after it injects a therapeutic agent into apatient; and FIG. 6C illustrates the exemplary wearable device in a PostInjection State after it has completed delivery of the therapeutic agentinto the patient or removed from the patient prior to completion ofdelivery of the therapeutic agent.

The wearable automatic injection device 600 includes a housing 635 forhousing a therapeutic agent cartridge assembly 610, containing a dose ofa therapeutic agent to be injected subcutaneously into a patient. In anexemplary embodiment, the outside of the therapeutic agent cartridgeassembly 610 may be provided with one or more ridges, and the inside ofthe housing 635 may be provided with one or more grooves or channelsthat provide a smooth pathway for the ridges of the cartridge assembly610 as the cartridge assembly moves within the housing 635. The one ormore ridges on the outside of the cartridge assembly 610 may take theform of raised lines on the cartridge assembly 610. The one or moregrooves or channels on the inside of the housing 635 may take the formedof U-shaped depressed or trough-like lines. The top portion of thegrooves or channels may be open so that the ridges may slide in and outof the top portion of the grooves or channels. In the linear insertionembodiment illustrated in FIGS. 6A-6C, the ridges and grooves/channelsmay be straight lines. In the rotary insertion embodiment illustrated inFIGS. 7A-7C, the ridges and grooves/channels may be lines that arecurved about the center of rotation, i.e., the pivot point of thecartridge assembly 610.

In another exemplary embodiment, the outside of the cartridge assembly610 may not have any ridges, and the inside of the housing 635 may nothave any grooves or channels.

The housing 635 preferably has an elongated configuration, though one ofordinary skill in the art will recognize that the housing 635 may haveany suitable size, shape and configuration for housing a hypodermicneedle couplable to a barrel portion of a therapeutic agent to beinjected. The housing 635 may be formed of any suitable materialincluding, but not limited to, plastic and other known materials. Inanother embodiment, the therapeutic agent cartridge 610 may be formed ofany compatible material suitable for sterilization including, but notlimited to, glass and other known materials.

The housing 635 includes an adhesive layer 640 disposed along a patientcontact portion of the housing 635 that is placed proximal to the skinof the patient or an article of clothing of the patient. In someembodiments, the adhesive layer 640 is configured to be placed on theskin of the patient to attach the housing 635 to the patient to delivera therapeutic agent. The adhesive layer 640 includes a non-adhesive tab645 which is not adhesive. The non-adhesive tab 645 may be gripped bythe patient and pulled to remove the adhesive layer 640 and thus thewearable automatic injection device 600 from the skin or clothing of thepatient.

Before the wearable automatic injection device 600 is put to use, e.g.,in the Pre-Injection state, the adhesive layer 640 is covered by aprotective film 650 which preserves the adhesive nature of the adhesivelayer 640. The protective film 650 may include a tab 655 which may begripped by the patient and pulled to remove the protective film 650 fromthe adhesive layer 640. This exposes the adhesive layer 640, allowingthe patient to attach the housing 635 to his or her skin or article ofclothing by placing the side with the adhesive layer 640 on the skin orthe article of clothing.

In exemplary embodiments, the protective film 650 (in FIG. 6A)/750 (inFIG. 7A) may include a linking member that is connected to the plungeractuator 630 (in FIG. 6A)/730 (in FIG. 7A). The linking member mayinclude a tether or other linkage mechanism. When the protective film650 (in FIG. 6A)/750 (in FIG. 7A) is removed, the linking member of theprotective film 650 (in FIG. 6A)/750 (in FIG. 7A) relieves staticfriction between the bung 615 (in FIG. 6A)/715 (in FIG. 7A) and theinterior wall of the barrel 605 (in FIG. 6A)/705 (in FIG. 7A), andtriggers the plunger actuator 630 (in FIG. 6A)/730 (in FIG. 7A).

The therapeutic agent cartridge assembly 610 may include a hollow barrelportion 605 for holding a therapeutically effective dose of thetherapeutic agent to be injected. The illustrative barrel portion 605 issubstantially cylindrical in shape, although one of ordinary skill inthe art will recognize that the barrel portion 605 may have any suitableshape or configuration. A bung 615 seals the dose of the therapeuticagent within the barrel portion 605.

The therapeutic agent cartridge assembly 610 may also include a hollowhypodermic needle 625 connectable to or connected to, and in fluidcommunication with, the barrel portion 605, through which the dose canbe ejected by applying pressure to the bung 615. The needle 625 may haveany suitable size, shape and configuration suitable for piercing theskin of the patient to deliver the therapeutic agent subcutaneously, andis not limited to the illustrative embodiment. Suitable needles may havea length configured or selected to provide an injection depth suitablefor the desired therapy. Subcutaneous injections typically penetrateabout six to ten millimeters into the skin. In an exemplary embodiment,needle 625 may have a length of about twelve mm and may be injected to adepth of about seven mm into the skin. In other exemplary embodiments,needle 625 may have lengths suitable for intradermal, othersubcutaneous, or intramuscular therapies. Suitable needles may have awall thickness suitable to provide sufficient mechanism strength, adiameter suitable to allow a desired flow rate of the injected substancewhile minimizing patient sensation, and a tip geometry suitable for thedesired therapy while minimizing patient sensation. Suitable needles maybe coated as needed to minimize patient sensation as allowed by therapy.Needle 625 may be covered and maintained in a septic condition by a softand rigid needle shield assembly 620.

In the exemplary embodiment illustrated in FIGS. 6A-6C, the needle 625projects substantially at a right angle to the longitudinal axis of thewearable device 600. In this exemplary embodiment, the barrel portion605 includes an elbow 607 that extends substantially at a right angle tothe longitudinal axis of the device 600. In this embodiment, the needle625 is connected to the elbow 607.

The wearable automatic injection device 600 may include a plungeractuator 630 for selectively actuating the bung 615 forwardly toward thedistal end of the therapeutic agent cartridge assembly 610 to inject thetherapeutically effective dose contained in the barrel portion 605 intothe patient. The plunger actuator 630 may employ an energy storage andcontrolled energy release mechanism to actuate the bung 615. In anexemplary embodiment, the plunger actuator 630 may include a biasingmechanism, e.g., a spring, that is retracted before injection and thatis released during injection to actuate the bung 615 forwardly in thebarrel portion 605. In another exemplary embodiment, the plungeractuator 630 may include a chemical gas generator, e.g., an expandingfoam, that is in a non-expanded phase before injection and that expandsduring injection to actuate the bung 615 forwardly in the barrel portion605 toward the distal end of the therapeutic agent cartridge assembly610. In other exemplary embodiments, the plunger actuator 630 may employcompressed gases, osmotic pressure, hydrogel expansion, etc. A dampingmechanism may be used to absorb energy, for example, an initial releaseof energy, and to provide a controlled release of energy during energyrelease by the plunger actuator 630 (in FIG. 6A)/730 (in FIG. 7A). Aflow restrictor placed in a fluid pathway between the needle and thebung 615 (in FIG. 6A)/715 (in FIG. 7A) may be used to further regulatethe rate of therapeutic agent delivery, e.g., where the plunger actuator630 (in FIG. 6A)/730 (in FIG. 7A) delivers an unconstrained springforce.

In an exemplary embodiment, the plunger actuator 630 may be advancedforwardly inside the barrel portion 605 in a constant linear motion. Anynumber of mechanisms, internal or external to the wearable automaticinjection device 600, may be used to provide a constant linear motionincluding, but not limited to, a stepper motor connected to a gear drivesystem. Other exemplary mechanisms for providing a substantiallyconstant linear motion in a controlled fashion are described withreference to FIGS. 24-45.

The bung 615 (in FIG. 6A)/715 (in FIG. 7A) and/or the plunger actuator630 (in FIG. 6A)/730 (in FIG. 7A) may include a linking member connectedto the retraction trigger. The linking member may include a tether orother linkage mechanism. The linking member may be of a suitable lengthsuch that, when the bung 615 (in FIG. 6A)/715 (in FIG. 7A) has beenmoved to the end of the cartridge assembly 610 (in FIG. 6A)/710 (in FIG.7A) (delivering a complete dose), the linking member triggers a latchthat in turn trips the retraction trigger.

Referring now to FIG. 6C, in an exemplary embodiment, the housing 635includes a skin sensor foot 660, which is a structure housed under or inthe portion of the housing 635 proximal to the injection site. Prior toinjection of the therapeutic agent and during injection, the skin sensorfoot 660 is retained within or forms a portion of the underside of thehousing 635. When the wearable automatic injection device 600 isattached to the injection site and activated, the skin sensor foot 660may be free to move but may be constrained by the injection site. Whenthe wearable automatic injection device 600 is removed from theinjection site, regardless of whether the drug delivery was completed,the skin sensor foot 660 is no longer constrained, and extends andprojects outside the periphery of the housing 635. This, in turn, tripsthe removal retraction trigger.

FIG. 6A illustrates the wearable automatic injection device 600 in aPre-Injection State, for example, as packaged and ready for use or asready for packaging. The device 600 may include a pre-fillable and/orpre-filled syringe or cartridge assembly. In an exemplary embodiment, ina pre-injection state, the syringe or cartridge assembly may be in aretracted position ready for use. In the Pre-Injection State, thetherapeutic agent cartridge assembly 610 is partially disposed withinthe housing 635 at an elevated location distal from the injection site,and the needle 625 is retracted within the housing 635. Visualindications to the patient that the wearable automatic injection device600 is not in operation may include a portion of the therapeutic agentcartridge assembly 610 projecting outside the housing 635 in thepre-injection state. The barrel portion 605 contains a dose of atherapeutic agent which is contained by the interior space definedbetween the wall or walls of the barrel portion 605 and the bung 615. Inan embodiment, the plunger actuator 630 stores energy.

FIG. 6B illustrates the wearable automatic injection device 600 in anInjection State ready to inject, injecting or just after injecting atherapeutically effective dose of a therapeutic agent, in which thetherapeutic agent cartridge assembly 610 is in a depressed position. Inthe depressed position, the therapeutic agent cartridge assembly 610 isdisposed within the housing 635 at a depressed location proximal to theinjection site, and the needle 625 projects outside the housing 635through an aperture in the housing 635 so that it can penetrate the skinat the injection site. In the Injection State, the therapeutic agentcartridge assembly 610 does not project outside the housing 635 toprovide a visual indication to the patient that the wearable automaticinjection device 600 is in operation. The plunger actuator 630 releasesits stored energy to actuate the bung 615. This cooperative movement ofthe plunger actuator 630 and the bung 615 ejects the therapeutic agentin the barrel portion 605 out through the needle 625.

FIG. 6C illustrates the wearable automatic injection device 600 in aPost Injection State, for example, after injecting a therapeuticallyeffective dose of the therapeutic agent or removal of the wearableautomatic injection device 600 from the patient before delivery of atherapeutically effective dose of the therapeutic agent, in which thetherapeutic agent cartridge assembly 610 is in a retracted position. Inthe retracted position, the therapeutic agent cartridge assembly 610 isdisposed within the housing 635 at an elevated location distal from theinjection site, and the needle 625 is retracted within the housing 635.A portion of the therapeutic agent cartridge assembly 610 projectsoutside the housing 635 to provide a visual indication to the patientthat the wearable automatic injection device assembly 600 is not inoperation (i.e., in a Post-Injection state). The barrel portion 605 maybe empty of the therapeutic agent, and the plunger actuator 630 may nolonger store energy.

The housing 635 includes a retraction mechanism that automaticallyraises the therapeutic agent cartridge assembly 610 from the InjectionState (depressed position shown in FIG. 6B) to the Post-Injection state(retracted position shown in FIG. 6C). In an exemplary embodiment, theretraction mechanism may include a biasing mechanism, e.g., a spring,that biases the cartridge assembly away from the injection site when theretraction mechanism is triggered.

The retraction mechanism includes an end-of-dose retraction triggerthat, when tripped, triggers the retraction mechanism. The end-of-doseretraction trigger is tripped when the therapeutically effective dose oftherapeutic agent in the wearable automatic injection device isdelivered. In an exemplary embodiment, the end-of-dose retractiontrigger may include a latch, e.g., a flexible plastic hook, that isreleased upon completed drug delivery. The retraction mechanism alsoincludes an early-removal retraction trigger that, when tripped,triggers the retraction mechanism. The early-removal retraction triggeris tripped when the wearable automatic injection device is removed fromthe injection site before the therapeutically effective dose oftherapeutic agent is completely delivered. In an exemplary embodiment,the early-removal retraction trigger may include a latch, e.g., aflexible plastic hook, that is released upon removal of the wearableautomatic injection device 600 from the injection site. The retractionmechanism is responsive to the end-of-dose retraction trigger andresponsive to the early-removal retraction trigger to automaticallyretract the cartridge assembly from the injection site.

FIGS. 7A-7C illustrate an exemplary embodiment of a wearable automaticinjection device 700 suitable for rotary insertion of the needle intothe skin of a patient. In rotary insertion, the end of a therapeuticagent cartridge assembly 710 bearing the needle 725 descends in a rotaryfashion about a pivot point to insert the needle 725 into the skin ofthe patient. More specifically, FIG. 7A illustrates the exemplarywearable device in a Pre-Injection State, for example, as packaged witha pre-filled and curved sterile hypodermic needle and barrel portionholding a therapeutic agent; FIG. 7B illustrates the exemplary wearabledevice while in an Injection State just before, while or just afterinjecting a therapeutic agent into a patient; and FIG. 7C illustratesthe exemplary wearable device in a Post Injection State after deliveryof the therapeutic agent into the patient or removal of the wearabledevice from the patient prior to completing delivery of the therapeuticagent to the patient.

The therapeutic agent cartridge assembly 710 is rotatably movable withinthe housing 735 about a pivot point 765 in the housing. In an exemplaryembodiment, the outside of the therapeutic agent cartridge assembly 710may be provided with one or more ridges, and the inside of the housing735 may be provided with one or more grooves or channels that provide apathway for the ridges of the cartridge 710 as the cartridge moveswithin the housing 735 amongst the various states. In another exemplaryembodiment, the outside of the cartridge assembly 710 is free of ridges,and the inside of the housing 735 is free of grooves or channels.

When the therapeutic agent cartridge assembly 710 is depressed into thehousing 735, the therapeutic agent cartridge assembly 710 movesrotatably downward about the pivot point 765 such that the needle 725becomes exposed and penetrates the skin of the patient. In thisexemplary embodiment, the needle 725 penetrates the skin of the patientat an angle offset from 90°. Similarly, when the therapeutic agentcartridge assembly 710 is retracted, the therapeutic agent cartridgeassembly 710 moves rotatably upward about the pivot point 765 such thatthe needle 725 retracts within the housing 735. The mechanism toimplement this rotational motion of the therapeutic agent cartridgeassembly 710 may be simpler and more robust than the mechanism requiredfor the linear insertion of FIGS. 6A-6C.

The needle 725 is curved, with a radius defined by the pivot point 765and the distance from the needle 715 to the pivot point 765 along thelongitudinal axis of the housing 735. The curvature of the needle 725increases the comfort of the patient during insertion of the needle. Theneedle 725 may be preferentially oriented with the sharp needle tipclosest to the pivot point 765.

Features in FIGS. 7A-7C similar to those illustrated in FIGS. 6A-6C aredescribed above in connection with FIGS. 6A-6C.

In exemplary embodiments, the therapeutic agent cartridge assembly 610and 720 of FIGS. 6A-6C and 7A-7C, respectively, may be pre-fillableand/or pre-filled with any volume of a therapeutic agent, e.g., atherapeutic antibody, desired for intradermal, subcutaneous, orintramuscular injections. In an exemplary embodiment, the cartridgeassembly 610 and 720 may be pre-fillable and/or pre-filled with a volumeof about 0.8-0.85 milliliters, although exemplary cartridge assembliesare not limited to these exemplary volumes. In another exemplaryembodiment, the cartridge assembly 610 and 720 may be pre-fillableand/or pre-filled with a volume of about 1 milliliter or more.

In exemplary embodiments, the wearable automatic injection device 600(in FIG. 6A)/700 (in FIG. 7A) may be used to inject the therapeuticallyeffective amount of therapeutic agent over a period of time ranging fromabout ten seconds to about twelve hours. In an exemplary embodiment, thetherapeutic agent may be delivered at a fixed rate for a delivery timeof between about five minutes and about thirty minutes. The wearableautomatic injection device 600 (in FIG. 6A)/700 (in FIG. 7A) may be usedto inject a volume of therapeutic agent in a single slow bolus.

The rate of delivery of the therapeutic agent may be dependent on theambient temperature. At room temperature, i.e., about 72° F., theaccuracy of the delivery time may range between about three percent andabout ten percent.

FIG. 8 is a flow chart of an exemplary method 800 of assembling anexemplary wearable automatic injection device 600 or 700. In step 805,the barrel portion 605/705, needle 625/725 and needle shield 620/720 aresterilized. In step 810, the barrel portion 605/705 is filled with adose of the therapeutic agent that is to be administered to the patient.In step 815, a sterile bung 615/715 is placed in the barrel portion605/705 to seal the therapeutic agent inside the barrel portion 605/705.The containment of the therapeutic agent inside the wearable automaticinjection device 600 or 700 by the sterile barrel portion 605/705, thesterile bung 615/715 and the needle shroud 620/720 maintains sterilityof the therapeutic agent and the needle 625/725. As such, the remainingcomponents of the wearable automatic injection device may be assembledin a non-sterile environment after the barrel portion 605/705 ispre-filled with a therapeutic agent. For example, in step 820, anon-sterile plunger actuator 630/730 is inserted behind the bung 615/715in the therapeutic agent cartridge assembly 610/710.

In step 825, the therapeutic agent cartridge assembly 610/710 isinserted into a non-sterile housing 635/735. The housing 635/735 may bepre-assembled with other non-sterile components, e.g., the adhesivelayer 640/740, the protective film 650/750, the skin sensor foot660/760. In exemplary embodiments, the barrel portion 605/705, theneedle 625/725, the needle shield 620/720 and the bung 615/715 of thetherapeutic agent cartridge assembly 610/710 provide the sterilitybarrier for the therapeutic agent and the subcutaneous contact surfaces.Thus, once the barrel portion 605/705 is filled with the therapeuticagent, the plunger 615/715 is inserted into the barrel portion 605/705and the needle shroud 620/720 is in place: assembly of the remainingportions of the therapeutic agent cartridge assembly 610/710 andassembly of the housing 635/735 do not require aseptic conditions. Notherapeutic agent transfer steps need to be performed by the user. FIGS.6A and 7A illustrate exemplary embodiments of the wearable assembledautomatic injection device 600/700 in a Pre-Injection state.

In step 830, the assembled wearable automatic injection device 600/700may be placed in an over-wrap, if necessary, and is then commerciallypackaged for sale.

FIG. 9 is a flow chart of an exemplary method 900 of using an exemplarywearable automatic injection device 600 or 700. The wearable automaticinjection device 600/700 packaged and pre-filled with a therapeuticagent is generally stored in refrigerated storage before use. In step905, the packaged wearable automatic injection device 600/700 is removedfrom storage. In step 910, the wearable automatic injection device600/700 is removed from its packaging and any over-wrap and warmed toroom temperature, e.g., by leaving the wearable device outside thepackaging at room temperature or by warming the wearable device. In step915, the patient confirms the therapeutic agent cartridge assembly610/710 includes a volume of the therapeutic agent in the wearabledevice 600/700 through an therapeutic agent inspection window disposedin the wearable device housing and may also confirm the clarity of thetherapeutic agent, if necessary. In step 920, the injection site on theskin of the patient is selected and prepared for the delivery of thetherapeutic agent. In step 925, the patient uses the wearable automaticinjection device 600/700 to inject the therapeutic agent into theinjection site. The steps generally involved within step 920 aredescribed below in connection with FIG. 10. In step 930, after thewearable automatic injection device 600/700 is removed from the patient,the removed wearable automatic injection device 600/700 is discarded inan appropriate manner.

FIG. 10 is a flow chart of an exemplary method 1000 of using anexemplary wearable automatic injection device 600 or 700 to inject atherapeutically effective amount of a therapeutic agent into a patient.Exemplary method 1000 is a detailed outline of step 920 in FIG. 9. Instep 1005, the patient removes the protective film 650/750 that coversand protects the adhesive layer 640/740 of the wearable automaticinjection device 600/700. In some exemplary embodiments, removal of theprotective film 650/750 also removes the needle shield 620/720 andexposes the needle 625/725 for injection. In some exemplary embodiments,removal of the protective film 650/750 also breaks static friction(i.e., stiction) between the bung 615/715 and the interior wall of thebarrel 605/705 and triggers the plunger actuator 630/730. In exemplaryembodiments, the protective film 650/750 may include a linking memberthat is connected to the plunger actuator 630/730. The linking membermay include a tether or other linkage mechanism. When the protectivefilm 650/750 is removed, the linking member of the protective film650/750 relieves static friction between the bung 615/715 and theinterior wall of the barrel 605/705, and triggers the plunger actuator630/730.

In step 1010, the patient applies the patient contact portion of thewearable automatic injection device 600/700 with the adhesive layer640/740 to the injection site (or an article of clothing around theinjections site) so that the wearable device is reliably retained on theinjection site during the injection of the therapeutically effectivedose of therapeutic agent.

In step 1015, once the wearable automatic injection device 600/700 isattached to the injection site, the therapeutic agent cartridge assembly610/710 is depressed from a ready position in the Pre-Injection State toa depressed position in the Injection State within the housing 635/735.In the ready position, the end of the therapeutic agent cartridgeassembly 610/710 bearing the needle 625/725 is retracted within thehousing 635/735 and is not exposed to the outside of the housing. Whendepressed, the end of the therapeutic agent cartridge assembly 610/710bearing the needle 625/725 is moved downward either linearly orrotationally within the housing 635/735 so that the needle 625/725emerges from an aperture in the housing 635/735 and is exposed. Thisallows the needle 625/725 to penetrate the skin of the patient to anappropriate depth for injection of the therapeutic agent. The downwardmovement of the therapeutic agent cartridge assembly 610/710 in thehousing 635/735 may be linear (i.e., a vertical downward movement) orrotary (i.e., in a circular movement about a pivot point). FIGS. 6B and7B illustrate exemplary embodiments of the wearable automatic injectiondevice 600 and 700 in an Injection state with the therapeutic agentcartridge 610/710 depressed into the housing 635/735 after step 1015 isperformed.

In an exemplary embodiment, the therapeutic agent cartridge assembly610/710 is depressed into the housing 635/735 by the patient manuallypushing down the therapeutic agent cartridge assembly 610/710. Inanother exemplary embodiment, the patient may activate an insertiontrigger, e.g., an insertion trigger button located in a convenientlyaccessible location such as the top of the housing 635/735, which causesan insertion trigger to automatically depress the therapeutic agentcartridge assembly 610/710 into the housing 635/735 and in turn, causethe needle 625/725 to pierce the skin of the patient. In an exemplaryembodiment, pressing the insertion trigger button may release a latch inthe insertion trigger that allows a spring to bias the cartridgeassembly 610/710 downwardly in the housing 635/735. The same motion ofthe cartridge assembly 610/710 may cause the needle 625/725 to beinserted into the injection site to an appropriate depth.

In an exemplary embodiment, depressing the therapeutic agent cartridgeassembly 610/710 triggers the plunger actuator 630/730 to begin movementof the bung 615/715 to cooperatively inject the therapeuticallyeffective dose into the patient. Depression of the therapeutic agentcartridge assembly 610/710 causes the plunger actuator 630/730 to breakthe static friction (i.e., stiction) between the bung 615/715 and theinside wall or walls of the barrel portion 605/705 and cause the bung615/715 to move forwardly toward the needle 625/725 in the therapeuticagent cartridge assembly 610/710 to deliver the therapeutic agent viathe needle 625/725. The plunger actuator 630/730 may overcome the bungstiction in one step and actuate the bung in a subsequent step, or theplunger actuator 630/730 may overcome the bung stiction and actuate thebung concurrently. In another exemplary embodiment, the plunger actuator630/730 is triggered not by depressing the therapeutic agent cartridge,but by the user activating an injection trigger, e.g., in the form of aninjection trigger button.

The rate of therapeutic agent delivery may depend on the characteristicsof the plunger actuator 630/730. The plunger actuator 630/730 may takethe form of several exemplary embodiments. In some exemplaryembodiments, the plunger actuator 630/730 may employ means of energystorage and release, e.g., biasing mechanisms (such as springs),compressed gases, chemical gas generators (such as expanding foams),osmotic pressure, hydrogel expansion, etc. A damping mechanism may beused to absorb energy, for example, an initial release of energy, and toprovide a more controlled release of energy during energy release by theplunger actuator 630/730. A flow restrictor placed in a fluid pathwaybetween the needle and the bung 615/715 may be used to further regulatethe rate of therapeutic agent delivery, e.g., where the plunger actuator630/730 delivers an unconstrained spring force. Thus, an appropriateplunger actuator 630/730 and an appropriate flow restrictor may beselected to deliver the dose at a controlled rate, e.g., in a singleslow bolus free of or substantially free of any burning sensation to thepatient.

In an exemplary embodiment, depressing the therapeutic agent cartridgeassembly 610/710 also arms the retraction mechanism which, whentriggered, retracts the therapeutic agent cartridge assembly 610/710into the housing 635/735.

In step 1020, the therapeutic agent cartridge assembly 610/710 isretracted from the depressed position to a retracted position in aPost-Injection State so that it protrudes outside the housing 635/735and the needle 625/725 is retracted within the housing 635/735 orprotected by the skin sensor foot 660/760 or both. FIGS. 6C and 7Cillustrate exemplary embodiments of automatic injection device 600 and700, respectively, in a retracted position after step 1020. Step 1020 isperformed either when the therapeutically effective dose of therapeuticagent is delivered or when the wearable automatic injection device600/700 is removed from the injection site before the therapeuticallyeffective dose is completely delivered.

Upon delivery of the therapeutically effective dose, the bung 615/715and/or the plunger actuator 630/730 trips the end-of-dose retractiontrigger of the retraction mechanism. The bung 615/715 and/or the plungeractuator 630/730 may include a linking member connected to theretraction trigger. The linking member may include a tether or otherlinkage mechanism. The linking member may be of a suitable length suchthat, when the bung 615/715 has been moved to the end of the cartridgeassembly 610/710 (delivering a complete dose), the linking membertriggers a latch that in turn trips the retraction trigger.

Once the end-of-dose retraction trigger is tripped, the retractionmechanism deploys the therapeutic agent cartridge assembly 610/710upward inside the housing 635/735 and away from the patient contactportion so that the therapeutic agent cartridge assembly 610/710 entersa Post-Injection State. In an exemplary embodiment, the movement of thetherapeutic agent cartridge assembly 610/710 from the injection state tothe post-injection state creates an audible sound, e.g., a “click,”which provides an aural indication of the completion of therapeuticagent delivery. Once retracted, the therapeutic agent cartridge assembly610/710 protrudes outside the housing 635/735 (as shown in FIGS. 6C and7C), which provides a visual indication of the state of the wearableautomatic injection device 600/700, for example, completion oftherapeutic agent delivery or a visual indication of the device in thePost-Injection State.

However, if the wearable device 600/700 is removed from the skin of thepatient before the completion of therapeutically effective dose of thetherapeutic agent, the skin sensor foot 660/760 extends to the outsideof the housing 635/735 and trips the early-removal retraction trigger ofthe retraction mechanism. Once the early-removal retraction trigger istripped, the retraction mechanism deploys the therapeutic agentcartridge assembly 610/710 upward in the housing 635/735 away from thepatient contact portion so that the therapeutic agent cartridge assembly610/710 is returned to a retracted position. In an exemplary embodiment,the plunger actuator 630/730 may continue to move forwardly in thetherapeutic agent cartridge 610/720 toward the needle 625/725 when thewearable device 600/700 is removed from the patient before completion ofdelivery of a therapeutically effective dose of the therapeutic agent.

In step 1025, upon retraction, an automatic needle lock engages with theinjection needle 625/725 to prevent redeployment of the needle 625/725to provide needle-stick protection. The needle lock may be a member thatprevents the needle 625/725 from exiting the housing 635/735 onceengaged, and may be located in the housing 635/735 near the needle625/725. Exemplary needle locks may include, but are not limited to, aplastic plate, a metal plate, a clip, etc.

III. EXEMPLARY NEEDLE SYSTEMS

Exemplary embodiments provide different exemplary needle assemblies forinjecting a dose of a therapeutic agent into a patient's skin. In someexemplary embodiments, an injection needle, coupled to a barrel portionof an exemplary automatic injection device containing the dose, may beinserted into the patient's skin to inject the dose into the patient'sskin. In other exemplary embodiments, a syringe needle may be coupled toa barrel portion containing the dose to conduct the dose out of thebarrel portion, and an injection needle coupled to the syringe needlemay be inserted into the patient's skin to inject the dose into thepatient's skin.

In some exemplary embodiments, as illustrated in FIGS. 11 and 12, asyringe may include a barrel portion and an injection needle coupled toa distal end of the barrel portion. The injection needle may be insertedinto the patient's skin to deliver a therapeutic agent contained in thebarrel portion of the syringe. The injection needle may be aligned atany suitable angle relative to the longitudinal axis of the barrelportion ranging from about 0 degrees to about 180 degrees.

FIG. 11 illustrates an exemplary syringe 1100 suitable for use in anexemplary automatic injection device. The syringe 1100 includes a barrelportion 1102 configured to hold a dose of a therapeutic agent andextending between a proximal end and a distal end along a longitudinalaxis L. A distal end of the barrel portion 1102 is coupled to aninjection needle 1104 that extends along the longitudinal axis L.

FIG. 12 illustrates an exemplary syringe 1200 suitable for use in anexemplary automatic injection device. The syringe 1200 includes a barrelportion 1202 configured to hold a dose of a therapeutic agent andextending between a proximal end and a distal end along a longitudinalaxis L. A distal end of the barrel portion 1202 may include an elbowportion 1204 that extends substantially at 90 degrees from thelongitudinal axis L. A distal end of the elbow portion 1204 is coupledto an injection needle 1206 that extends substantially at 90 degreesfrom the longitudinal axis L. One of ordinary skill in the art willrecognize that exemplary automatic injection devices may includeinjection needles that extend along the longitudinal axis L of thesyringe or that extend at any suitable angle relative to thelongitudinal axis L of the syringe. Exemplary angles may include, butare not limited to, about 70 degrees to about 110 degrees.

In some exemplary embodiments, as illustrated in FIGS. 13 and 14, asyringe may include a barrel portion and an injection needle coupled toa distal end of the barrel portion. The injection needle may be insertedinto a patient's skin to deliver a therapeutic agent contained in thebarrel portion of the syringe. The injection needle may be aligned atany suitable angle relative to the longitudinal axis of the barrelportion ranging from about 0 degrees to about 180 degrees.

In some exemplary embodiments, as illustrated in FIGS. 13 and 14, asyringe may include a barrel portion and an injection needle coupleddirectly or indirectly to a distal end of the barrel portion. Thesyringe needle may convey a therapeutic agent contained in the barrelportion of the syringe to the injection needle, and the injection needlemay deliver the therapeutic agent into a patient's skin. A couplingbetween the syringe needle and the injection needle may be provided byone or more intermediate components. An exemplary coupling component mayinclude, for example, an adapter, provided between the distal end of thebarrel portion and the injection needle.

FIG. 13 illustrates an exemplary syringe 1300 suitable for use in anexemplary automatic injection device. The syringe 1300 includes a barrelportion 1302 configured to extend from a proximal end to a distal endalong a longitudinal axis L and configured to hold a dose of atherapeutic agent. A distal end of the barrel portion 1302 is coupled toa hollow syringe needle 1304. The syringe needle 1304 is, in turn,coupled to a hypodermic injection needle 1306 through an exemplaryintermediate adapter 1308. More specifically, a proximal portion of theadapter 1308 is coupled to the syringe needle 1304 and a distal portionof the adapter 1308 is coupled to the injection needle 1306. The adapter1308 may establish a substantially 90 degree alignment between thelongitudinal axis L of the barrel portion 1302 and the hypodermicinjection needle 1306.

The exemplary adapter 1308 is a component that includes a first portion1310 that extends from the barrel portion 1302 substantially parallel tothe longitudinal axis L, and a second portion 1312 that extends from thefirst portion 1310 substantially perpendicular to the longitudinal axisL. More specifically, a proximal end of the first portion 1310 iscoupled to a distal end of the barrel portion 1302. In an exemplaryembodiment, the proximal end of the first portion 1310 may envelope thedistal end of the barrel portion 1302. A distal end of the first portion1310 is coupled to a proximal end of the second portion 1312. A distalend of the second portion 1312 is coupled to a proximal end of theinjection needle 1306. In an exemplary embodiment, the first portion1310 and the second portion 1312 of the adapter 1308 may be formedintegrally.

Exemplary adapters may be formed of a rigid material including, but notlimited to, plastic materials, steel, and the like. Exemplary adaptersmay alternatively be formed of a flexible material including, but notlimited to, rubber and the like.

The configuration of the adapter 1308 coupled to the injection needle1306 allows the injection needle 1306 to extend at about 90 degreesrelative to the longitudinal axis L of the syringe. This configurationsimplifies the manufacturing of the wearable automatic injection deviceas it eliminates the need for a bent injection needle. The exemplaryinjection needle 1306 maintains a low profile against the patient whileallowing for proper insertion into the patient's skin during aninjection in an injection state. One of ordinary skill in the art willrecognize that exemplary injection needles may be bent from thelongitudinal axis of the syringe to any suitable angle not limited toabout 90 degrees, e.g., about 70 degrees to about 110 degrees.

In some exemplary embodiments, one or more fluid conduits may bedisposed between the syringe needle and the injection needle to allow aflow of the therapeutic agent from the barrel portion to the injectionneedle through the syringe needle. Any suitable fluid conduit or fluidtransfer mechanism may be used to establish the one or more fluidconduits between the syringe needle and the injection needle. In anexemplary embodiment, a pierceable septum in its intact state mayseparate the syringe needle from fluid communication from the injectionneedle. When the syringe needle pierces the septum during an injectionin an injection state, fluid communication may be established betweenthe syringe needle and the injection needle through the fluid conduit.

FIG. 14 illustrates a portion of an exemplary automatic injection devicein which a fluid conduit couples a syringe needle and an injectionneedle. The device includes a syringe or cartridge assembly having abarrel portion 1400 holding a dose of a therapeutic agent. A distal endof the barrel portion 1400 is coupled to a syringe needle 1402. Atransfer mechanism 1404 is provided in contact with or in the vicinityof the syringe needle 1402, and also in contact with or in the vicinityof an injection needle (not pictured). The transfer mechanism 1404includes a fluid conduit or passageway 1406 that establishes fluidcommunication between the syringe needle 1402 and the injection needle.

In an exemplary embodiment, the transfer mechanism 1404 includes apierceable septum 1408 that separates the syringe needle 1402 from thefluid conduit 1406 in the transfer mechanism 1404 before an injection ina pre-injection state. In an exemplary embodiment, during an injectionin an injection state, the syringe or cartridge may be moved toward thetransfer mechanism 1404 so that the syringe needle 1402 pierces theseptum 1408 to create a fluid communication path among the barrelportion 1400, the fluid conduit 1406 of the transfer mechanism 1404, andthe injection needle. The therapeutic agent may thereby flow out of thebarrel portion 1400 through the syringe needle 1402 into the fluidconduit 1406. The therapeutic agent may then be transmitted through thefluid conduit 1406 into the injection needle for delivery of thetherapeutic agent to a patient.

FIG. 15 illustrates an exemplary transfer mechanism 1500 for providing afluid conduit 1502 between a syringe needle (not pictured) and aninjection needle (not pictured). The fluid conduit 1502 may include acentrally extending channel 1504 through which the therapeutic agentflows from the syringe needle to the injection needle, and raised wallportions 1506 extending along the edges of the channel 1504 in order toconstrain the fluid to the channel 1504. The fluid conduit 1502 may takeany suitable form and dimension. In the illustrative embodiment, thefluid conduit 1502 has a first substantially straight portion 1508aligned at about 90 degrees from a second substantially straight portion1510.

The fluid conduit 1502 may include a fluid inlet 1512 for entry of thetherapeutic agent from the syringe needle, and a fluid outlet 1514 forexit of the therapeutic agent into the injection needle. The fluid inlet1512 may be coupled directly or indirectly to the proximal end of asyringe needle. In an exemplary embodiment, a pierceable septum (notpictured) may be provided at the fluid inlet 1512 to prevent fluid flowfrom the syringe needle when the septum is intact, and to allow fluidflow from the syringe needle when the septum is pierced by the syringeneedle. The fluid outlet 1514 may be coupled directly or indirectly tothe distal end of the injection needle in order to establish a fluidflow path between the fluid conduit 1502 and the injection needle.

Alternatively, 1512 may be used as the fluid outlet and 1514 may be usedas the fluid inlet. In this exemplary embodiment, fluid inlet 1514 maybe coupled directly or indirectly to a syringe needle, and fluid outlet1512 may be coupled directly or indirectly to an injection needle.

The transfer mechanism 1500 may be formed of two housing portions 1516and 1518 stacked together. In an exemplary embodiment, the fluid conduit1502 may be formed on the surface of portion 1516, and portion 1518 maybe stacked over the fluid conduit 1502 so as to seal the edges of thefluid conduit 1502 in order to prevent fluid leakage from the fluidconduit. Compression between the two housing portions 1516 and 1518 maybe provided by one or more mechanical interlocking mechanism, forexample, one or more fasteners, snaps, chemical bonding, ultrasonicwelding, and others.

The fluid conduit 1502 may be formed on the surface of the housingportion 1516 using any suitable technology. In an exemplary embodiment,the raised wall portions 1506 of the fluid conduit 1502 may be formed ofa low durometer material molded as a gasket to seal the flow path of thetherapeutic agent. In another exemplary embodiment, laser welding may beused to trace a path around the perimeter of the channel 1504 in orderto simultaneously create a seal around the channel 1504 and bond the twohousing portions 1516 and 1518 together.

FIG. 16 illustrates an exemplary transfer mechanism 1600 for providing afluid conduit 1602 between a syringe with a syringe needle 1604 coupledto a barrel portion 1606 and an injection needle (not pictured). Thetransfer mechanism 1600 may include a first portion 1608 having a septum1610 provided in the vicinity of the syringe needle 1604.

The first portion 1608 of the transfer mechanism 1600 may include aninternal hollow space for accommodating the therapeutic agent and aninlet port 1612 coupled to one end of a hollow tube 1614. Another end ofthe hollow tube 1614 is coupled directly or indirectly (for example,through a second portion similar to first portion 1608) to the injectionneedle. The hollow tube 1614 provides a fluid path from the syringeneedle 1604 to the injection needle. The hollow tube 1614 may take anysuitable form, alignment and dimension. In the illustrative embodiment,the hollow tube 1614 extends substantially at right angles to thelongitudinal axis of the barrel portion 1606.

In an exemplary embodiment, the transfer mechanism 1600 may be moveableupward and/or downward along the vertical axis. In this embodiment,before an injection in a pre-injection state (for example, when thesyringe needle is covered by a needle cover), the transfer mechanism1600 may be in a vertically raised position above the syringe needle1604 such that the syringe needle 1604 is not aligned with the septum1610 in the transfer mechanism 1600, thereby preventing fluidcommunication between the syringe needle 1604 and the transfer mechanism1600. At the beginning of an injection (for example, upon removal of thesyringe cover from the syringe needle 1604), the transfer mechanism 1600may be automatically lowered to a vertically lowered position such thatthe syringe needle 1604 becomes aligned with the septum 1610 in thetransfer mechanism 1600, thus allowing the syringe needle 1604 to piercethe septum 1610. Exemplary embodiments may provide any suitableactuation mechanism for lowering the transfer mechanism 1600 from thevertically raised position to the vertically lowered position at thebeginning of an injection.

In an exemplary embodiment, the syringe needle 1604 may be initiallycoupled to or provided immediately adjacent to the first portion 1608.In another embodiment, the syringe may be in a retraction positionwithin the wearable automatic injection device and the syringe needle1604 may be initially separated from the first portion 1608 of thetransfer mechanism 1600. In this embodiment, before an injection in apre-injection state, the syringe needle 1604 may be separated from theseptum 1610 in the first portion 1608 and may not be in fluidcommunication with the transfer mechanism 1600. At the beginning of aninjection, the syringe may be moved forwardly by a cartridge or syringeactuator to an extended position within the device, and the syringeneedle 1604 may pierce the septum 1610, allowing the therapeutic agentto flow from the barrel portion 1606 to the transfer mechanism 1600.Exemplary embodiments may provide any suitable syringe or cartridgeactuation mechanism for advancing the barrel portion and/or thecartridge assembly within the housing between the retracted position andthe extended position in order to pierce the septum and convey thetherapeutic agent to the patient's skin through the injection needle.

An advantage of the exemplary transfer mechanism 1600 is that themotions of the syringe needle 1604 and the injection needle aredecoupled and independent from each other. For example, the mechanismcoupling the syringe needle 1604 to the inlet port 1612 need not takeinto consideration how this coupling would affect the outlet of thetransfer mechanism 1600 coupled to the injection needle.

FIG. 17 illustrates an exemplary transfer mechanism 1700 for providing afluid conduit between a syringe having a syringe needle 1704 coupled toa barrel portion 1706 and an injection needle (not pictured). Thetransfer mechanism 1700 may include an inlet portion (not pictured)couplable to the syringe needle 1704 and an outlet portion (notpictured) couplable to the injection needle. A hollow tube 1708, forexample, a jumper tube, may be used to couple the inlet portion of thetransfer mechanism to the outlet portion of the transfer mechanism. Thehollow tube 1708 provides a fluid path from the syringe needle 1704 tothe injection needle. The hollow tube 1708 may take any suitable form,alignment and dimension. In the illustrative embodiment, the hollow tube1708 extends substantially at right angles to the longitudinal axis ofthe barrel portion 1706.

In an exemplary embodiment, the inlet portion of the transfer mechanism1700 may include a septum (not pictured) provided in the vicinity of thesyringe needle 1704. Piercing of the septum by the syringe needle 1704may establish fluid communication between the barrel portion 1706 andthe transfer mechanism 1700. In an exemplary embodiment, the outletportion of the transfer mechanism may include a septum (not pictured)provided in the vicinity of the injection needle. Piercing of the septumby the injection needle may establish fluid communication between thetransfer mechanism 1700 and the patient's skin.

In an exemplary embodiment, the transfer mechanism 1700 may be moveableupward and/or downward along the vertical axis. In this embodiment,before an injection in a pre-injection state (for example, when thesyringe needle is covered by a needle cover), the transfer mechanism1700 may be in a vertically raised position above the syringe needle1704 such that the syringe needle 1704 is not aligned with the septum inthe transfer mechanism 1700, thereby preventing fluid communicationbetween the syringe needle 1704 and the transfer mechanism 1700. At thebeginning of an injection (for example, upon removal of the syringecover from the syringe needle 1704), the transfer mechanism 1700 may beautomatically lowered to a vertically lowered position such that thesyringe needle 1704 becomes aligned with the septum in the transfermechanism 1700, thus allowing the syringe needle 1704 to pierce theseptum. Exemplary embodiments may provide any suitable actuationmechanism for lowering the transfer mechanism 1700 from the verticallyraised position to the vertically lowered position at the beginning ofan injection.

In an exemplary embodiment, the syringe needle 1704 may be initiallycoupled to or provided immediately adjacent to the first portion 1708.In another embodiment, the syringe may be in a retraction positionwithin the wearable automatic injection device and the syringe needle1704 may be initially separated from the transfer mechanism 1700. Inthis embodiment, before an injection in a pre-injection state, thesyringe needle 1704 may be separated from the septum and may not be influid communication with the transfer mechanism 1700. At the beginningof an injection, the syringe may be moved forwardly by a cartridge orsyringe actuator to an extended position within the device, and thesyringe needle 1704 may pierce the septum, allowing the therapeuticagent to flow from the barrel portion 1706 to the transfer mechanism1700. Exemplary embodiments may provide any suitable syringe orcartridge actuation mechanism for advancing the barrel portion and/orthe cartridge assembly within the housing between the retracted positionand the extended position in order to pierce the septum and convey thetherapeutic agent to the patient's skin through the injection needle.

In the exemplary embodiments illustrated in 15-17, a tight and reliablefluid path conveys the therapeutic agent from the barrel portion of asyringe or cartridge through a pierced septum and a tube or channel in atransfer mechanism and eventually into an injection needle. Thisconfiguration allows the syringe needle assembly and the injectionneedle assembly to move independently of each other, which facilitatesretraction of the injection needle into the housing in a post-injectionstate after an injection has been performed, while leaving the syringeneedle in a position in which it pierces the septum.

FIGS. 18A and 18B illustrate an exemplary wearable automatic injectiondevice including a syringe and an exemplary transfer mechanism. FIG. 18Aillustrates a perspective view of the device. FIG. 18B illustrates adisassembled view showing the components of the device. The automaticinjection device 1800 includes a housing portion 1802 that includes anadhesive layer 1804 at a patient contact region that may be removed toattach the device to a patient's body or clothing.

The housing portion 1802 holds a syringe 1806 in a stationary ormoveable manner in the device 1800. The syringe 1806 holds a dose of atherapeutic agent and that is coupled to a syringe needle 1808 at itsdistal end. The syringe needle 1808 may extend substantially along thelongitudinal axis of the syringe 1806. In a packaged pre-injectionstate, the syringe needle 1808 may be covered by a syringe needle cover1805, which may be removed by a patient before an injection. In aninjection state, the syringe needle 1808 may be uncovered. In anexemplary embodiment, removal of the adhesive layer 1804 may also removethe syringe needle cover 1805.

An injection button 1810 is provided in the vicinity of the syringeneedle 1808. The injection button 1810 includes holds an injectionneedle 1812 at substantially 90 degrees relative to the syringe needle1808, and includes a transfer mechanism that provides a fluid conduitbetween the syringe needle 1808 and the injection needle 1812. In apackaged pre-injection state, the injection needle 1812 may be coveredby an injection needle cover 1813, which may be removed by a patientbefore an injection. In an injection state, the injection needle 1812may be uncovered. In an exemplary embodiment, removal of the adhesivelayer 1804 may also remove the injection needle cover 1813.

The injection button 1810 also includes a septum 1811 that prevents thesyringe needle 1808 from establishing fluid communication with the fluidconduit in the injection button 1810. A cover 1813 may be provided tocover the septum 1811 in a pre-injection state, which may be removed bya patient before an injection. In an exemplary embodiment, the septumcover 1813 and the syringe needle cover 1805 may be coupled so thatremoval of one also removes the other.

In an exemplary embodiment, in a pre and post-injection state, thesyringe needle cover 1805 may cover the syringe needle 1808, and theinjection button 1810 may be in a vertically raised position asdisplaced by the syringe needle cover 1805 such that the injectionneedle 1812 is retracted within the housing 1802. In this state, theseptum 1811 of the injection button 1810 may be vertically above thesyringe needle 1808. In addition, the syringe 1806 may be in a retractedposition along the longitudinal axis of the assembly 1806 spaced fromthe septum 1811 of the injection button 1810.

When the syringe needle cover 1805 is removed from the syringe needle1808, the injection button 1810 is lowered to a vertically loweredposition such that the injection needle 1812 protrudes outside thehousing 1802 into the patient contact region. In an exemplaryembodiment, the injection button 1810 may be automatically lowered bythe removal of the syringe needle cover 1805. In another exemplaryembodiment, the injection button 1810 is lowered by the patient pushingdownward on the injection button 1810.

In an exemplary embodiment, the lowering of the injection button 1810aligns the syringe needle 1808 with the septum 1811 of the injectionbutton 1810. The lowering of the injection button 1810 also triggers asyringe actuator that advances the syringe 1806 along its longitudinalaxis toward the septum 1811 of the injection button 1810. This causesthe syringe needle 1808 to pierce the septum 1811 and establish fluidcommunication with the injection needle 1812.

FIGS. 19A and 19B illustrate an exemplary wearable automatic injectiondevice including a syringe and an exemplary transfer mechanism. FIG. 19Aillustrates a side view of the device. FIG. 19B illustrates aperspective view showing the components of the device. The automaticinjection device 1900 includes a housing 1902 holding a syringe 1904 ina stationary of moveable manner relative to the housing 1902. Aninjection button 1906 is provided in the housing 1902 in the vicinity ofthe syringe 1904 and holds an injection needle (not pictured). Thehousing 1902 includes an adhesive layer 1908 for attachment at a patientcontact region.

Other components in the device 1900 similar to the components in thedevice 1800 are described with reference to FIGS. 18A and 18B.

FIGS. 20A-20C illustrate an exemplary wearable automatic injectiondevice including a cartridge assembly and an exemplary transfermechanism. FIG. 20A illustrates a perspective view of the device. FIG.20B illustrates a top view of the device. FIG. 20C illustrates a sideview of the transfer mechanism of the device. The automatic injectiondevice 2000 includes a housing 2002 having an adhesive layer 2003 forattachment at a patient contact region. The housing 2002 holds acartridge 2004 in a stationary or moveable manner relative to thehousing 2002. The cartridge 2004 is configured to hold a dose of atherapeutic agent.

An injection button 2006 is provided in the housing 2002 in the vicinityof the cartridge 2004. The injection button 2006 may hold or be coupledto an injection needle 2008 extending substantially at 90 degreesrelative to the longitudinal axis of the cartridge 2004 and a syringeneedle 2010 extending substantially parallel to the longitudinal axis ofthe cartridge 2004. The injection button 2006 may form or include atransfer mechanism that establishes fluid communication between thecartridge 2004 to the injection needle 2008 through the syringe needle2010.

The injection button 2006 may include a housing engagement portion 2012that engages with a housing portion 2014 when the injection button 2006is pressed down during an injection in an injection state. In anexemplary embodiment illustrated in FIG. 20C, the engagement between thehousing engagement portion 2012 and the housing portion 2014 causes thehousing portion 2014 to move parallel to the longitudinal axis of thecartridge 2004 toward the distal end of the cartridge 2004, thusallowing the syringe needle 2010 to establish fluid communication withthe barrel portion of the cartridge 2004. In another exemplaryembodiment, the engagement between the housing engagement portion 2012and the housing portion 2014 causes the cartridge 2004 to move parallelto the longitudinal axis of the cartridge 2004 toward the syringe needle2010, thus allowing the syringe needle 2010 to establish fluidcommunication with the barrel portion of the cartridge 2004.

Other components in the device 2000 similar to the components in thedevice 1800 are described with reference to FIGS. 18A and 18B.

FIGS. 21A-21C illustrate an exemplary wearable automatic injectiondevice including an exemplary cartridge assembly. FIG. 21A illustrates aperspective view of the exemplary wearable automatic injection device.FIG. 21B illustrates a sectional view of the cartridge assembly takenalong a longitudinal axis. FIG. 21C illustrates a transparent top viewof the transfer mechanism of the device. The automatic injection device2100 includes a housing 2102 having an adhesive layer 2103 forattachment at a patient contact region. The housing 2102 holds acartridge 2104 in a stationary or moveable manner relative to thehousing 2102. The cartridge 2104 is configured to hold a dose of atherapeutic agent. A proximal end of the cartridge 2104 includes a bung2106 and a distal end of the cartridge 2104 includes a septum 2108 thatcooperatively seal the dose within the cartridge 2104.

An injection button 2110 is provided in the housing 2102 in the vicinityof the cartridge 2104. The injection button 2110 holds an injectionneedle at a proximal end that extends substantially at 90 degreesrelative to the longitudinal axis of the cartridge 2104. The injectionbutton 2110 is coupled to a transfer mechanism 2111 that holds a syringeneedle 2112 in the vicinity of the cartridge 2104. The syringe needle2112 extends substantially parallel to the longitudinal axis of thecartridge 2104. The transfer mechanism 2111 includes a fluid conduit toestablish fluid communication between the cartridge 2104 to theinjection needle 2108 through the syringe needle 2110. In apre-injection state, the syringe needle 2112 may extend partly into adistal end of the cartridge 2104 but may be spaced from the septum 2108.In an injection state, the bung 2106 may be moved within the cartridge2104 such that the fluid pressure in the cartridge 2104 moves the septum2108 forward toward the syringe needle 2112. This causes the syringeneedle 2112 to pierce the septum 2108 and establishes fluidcommunication between the cartridge 2104 and the injection needlethrough the syringe needle 2112.

Other components in the device 2100 similar to the components in thedevice 1800 are described with reference to FIGS. 18A and 18B.

FIG. 22 illustrates an exemplary syringe or cartridge actuator 2200 thatmay be used to advance a syringe 2202 or a cartridge assembly from aretraction position to an extended position within the housing of awearable automatic injection device. A proximal end of the barrelportion and/or the cartridge assembly may be coupled to a biasing member2204, for example, a drive spring, that applies a force on the barrelportion of the syringe and/or the cartridge assembly to move the barrelportion and/or the cartridge assembly toward a septum in a transfermechanism (not pictured). The syringe or cartridge actuator 2200 maycounter the biasing force of the biasing member, and may hold and lockthe barrel portion and/or the cartridge assembly in a retracted positionin a stable and reliable manner.

When triggered, the syringe or cartridge actuator 2200 may allow thebarrel portion and/or the cartridge assembly to move forward toward theseptum under the force of the biasing member. In an exemplaryembodiment, the syringe or cartridge actuator 2200 may be configuredand/or set to a certain distance to control the level of triggeringforce required to advance the barrel portion and/or the cartridgeassembly from the retracted position to the extended position.

Any suitable trigger mechanism may be used to trigger the syringe orcartridge actuation systems. In an exemplary embodiment, the triggermechanism may automatically trigger the syringe or cartridge actuationsystem when the wearable automatic injection device moves from apre-injection state to an injection state. In an exemplary embodiment,the downward vertical movement of an injection button within the housingto provide a fluid path between the syringe or cartridge assembly andthe injection needle may provide a trigger force to trigger the plungeractuation system. In another exemplary embodiment, the forward movementof the syringe or cartridge assembly within the housing to establish afluid path between the syringe or cartridge assembly and the injectionneedle may provide a trigger force to trigger the syringe or cartridgesystem. In another exemplary embodiment, the syringe or cartridge systemmay be manually triggered by a user.

Before an injection in a pre-injection state, a needle cover, forexample, a soft and rigid needle shield assembly (not pictured),provided at the distal end of the syringe may protectively cover thesyringe needle. At this stage, since the syringe needle is covered withthe needle cover, the distal end of the syringe has a first greaterdiameter. As such, the transfer mechanism including the septum ismaintained in a vertically raised position above the needle cover, andthe septum is not aligned with the syringe needle. When the needle coveris removed from the syringe in preparation for an injection (forexample, manually by a user or by an automatic mechanism), the transfermechanism is allowed to lower to a vertically lowered position since itis not longer kept displaced by the rigid needle shield, and the septumin the transfer mechanism is aligned with the syringe needle. Theremoval of the needle cover thus lowers the transfer mechanism from itsraised position to its lowered position. The lowering of the transfermechanism, in turn, applies a trigger force to the syringe or cartridgeactuator 2200 and operates as the trigger mechanism for the syringe orcartridge actuator 2200.

FIG. 23 illustrates an exemplary syringe or cartridge actuator 2300including a first portion 2302, a second portion 2304 and a hingeportion 2306 provided between the first and second portions. The hingeportion 2306 allows the first and second portions to rotate about thehinge relative to each other. In different rotational configurations,the first and second portions may have exemplary angles of between about0 degrees and about 180 degrees between each other. The actuator 2300may be coupled to the syringe and to the septum and/or the transfermechanism. When the septum and/or transfer mechanism is in its firstraised position, the actuator 2300 may hold the syringe in place in itsretracted position. When the septum and/or transfer mechanism is in itssecond lowered position, the actuator 2300 may release the syringe sothat the biasing member may push the syringe forward to its extendedposition in order to pierce the septum.

IV. EXEMPLARY PLUNGER ACTUATION SYSTEMS AND NEEDLE RETRACTION SYSTEMS

Exemplary embodiments provide plunger actuation systems for actuating abung in a barrel portion of a wearable automatic injection device sothat the bung moves forwardly within the barrel portion and expels adose of a therapeutic agent contained in the barrel portion. Anysuitable trigger mechanism may be used to trigger the plunger actuationsystems. In an exemplary embodiment, the trigger mechanism mayautomatically trigger the plunger actuation system when the wearableautomatic injection device moves from a pre-injection state to aninjection state. In an exemplary embodiment, the downward verticalmovement of an injection button within the housing to provide a fluidpath between the syringe or cartridge assembly and the injection needlemay provide a trigger force to trigger the plunger actuation system. Inanother exemplary embodiment, the forward movement of the syringe orcartridge assembly within the housing to establish a fluid path betweenthe syringe or cartridge assembly and the injection needle may provide atrigger force to trigger the plunger actuation system. In anotherexemplary embodiment, the plunger actuation system may be manuallytriggered by a user.

Certain other exemplary embodiments provide plunger actuation devicesand systems that cause actuation of the syringe plunger at a slow ratein order to deliver the therapeutic agent to a patient at a slow rate.Exemplary slow embodiments may deliver therapeutic agent volumes ofabout 0.1 milliliters to about 1 milliliter or more in about fiveminutes to about thirty minutes, although exemplary delivery rates arenot limited to this exemplary range.

Exemplary embodiments may provide a linear delivery profile for thetherapeutic agent so that the delivery rate is substantially constantover time. In some cases, a linear delivery profile may reducediscomfort experienced by the patient.

FIG. 24 illustrates a schematic of a portion of an exemplary automaticinjection device 2400 including a plunger actuation mechanism thatemploys a fusee and a viscous damping mechanism. The wearable automaticinjection device 2400 includes a housing 2402 having a platform 2410that is a mechanical structure for holding a syringe or cartridgeassembly 2404 in place within the wearable automatic injection device2400. The syringe or cartridge 2404 includes a barrel portion forholding a dose of a therapeutic agent and a bung 2408 for sealing thedose within the barrel portion. A plunger actuation mechanism 2406 isprovided for moving the bung 2408 within the barrel portion forexpelling the dose from the barrel portion. A damping mechanism 2422,for example, a viscous damper, is provided to regulate the motion of thebung 2408 so that the therapeutic agent is delivered in a linearfashion, i.e., at a substantially constant flow rate. A gear train 2420including one or more gears may be provided to couple the plungeractuation mechanism 2406 to the damping mechanism 2422. The gear train2420 may include any number of suitable gears to provide any suitablegearing ratio.

The platform 2410 of the wearable automatic injection device 2400 may bestationary or moveable. In an exemplary embodiment, the platform 2410may be a substantially box-shaped or cylindrical structure with aninternal space for accommodating the syringe or cartridge 2404. Theperipheral walls surrounding the internal space may be configured tohold a syringe or a cartridge assembly 2404 in place. The platform 2410may include one or more clamping mechanism 2412 for holding the syringeor cartridge 2404 in place. The platform 2410 may also include a flangebearing 2414 provided at the proximal end of the syringe or cartridge2404. A flange provided at the proximal end of the syringe or cartridge2404 may slide backward against the flange bearing 2414.

In an exemplary embodiment, the platform 2410 may hold the syringe orcartridge 2404 stationary within and relative to the platform 2410. Inanother exemplary embodiment, the platform 2410 may allow the syringe orcartridge 2404 to move relative to the platform 2410, for example,toward or away from a fluid transfer mechanism (not pictured). In thisexemplary embodiment, the internal space of the platform 2410 mayinclude one or more grooves, tracks or channels for facilitating themovement of the syringe or cartridge 2404 within the platform 2410. Inan exemplary embodiment, the platform 2410 may include a window 2416,for example, a cutout or a transparent portion, in order to allow thepatient to view the syringe or cartridge 2404.

One or more plunger actuators 2406 may be provided in the vicinity ofthe syringe or cartridge 2404 for storing energy and providing a forcefor driving a bung 2408 within the syringe or cartridge 2404 toward thedistal end of the syringe or cartridge 2404. In an exemplary embodiment,a plunger actuator 2406, for example, a helical compression spring, maybe used to drive the bung 2408. The plunger actuator 2406 may beprovided at least partly within the syringe or cartridge 2404. Before aninjection in a pre-injection state, the plunger actuator 2406 may bemaintained in a compressed state. At the beginning of an injection orduring an injection in an injection state, the plunger actuator 2406 maybe allowed to expand from the compressed state to a released state. Theexpansion of the plunger actuator 2406 may push the bung 2408 toward thedistal end of the syringe or cartridge 2404, thus expressing thetherapeutic agent from the syringe or cartridge 2404. Advantageously,the configuration of the plunger actuator 2406 within the syringe orcartridge 2404 does not add to the length of the housing required tohold the syringe or cartridge 2404. However, in some exemplaryembodiments, the plunger actuator 2406 may not provide a constant forceto drive the bung 2408.

In another exemplary embodiment, a spiral spring may be used to drivethe bung 2408. The spiral spring may be provided outside but alongsidethe syringe or cartridge 2404 of within the platform 2410, which may addto the space requirement of the housing 2402. Before an injection in apre-injection state, the spring may be maintained in a compressed state.At the beginning of an injection or during an injection in an injectionstate, the spring may be allowed to expand from the compressed state toa released state. The expansion of the spring may push the bung 2408toward the distal end of the syringe or cartridge 2404, thus expressingthe therapeutic agent from the syringe or cartridge 2404.Advantageously, the spiral spring may provide a substantially constantforce to drive the bung 2408.

One or more damping mechanisms may be provided for regulating therelease of energy in the plunger actuator 2406 in order to control thedelivery rate and/or the delivery time for delivering the therapeuticagent. In an exemplary embodiment, to achieve a slow and/or controlleddelivery, the plunger actuator 2406 is prevented from acceleratingwithout resistance from its compressed state to a released state. Themovement of the plunger actuator 2406 may be maintained at a constantspeed, for example, by providing linear damping values. Any suitablemechanism may be used to provide resistance against the acceleration ofthe plunger actuator 2406. In an exemplary embodiment, a rotary viscousdamper 2422 may be used to resist the acceleration of the plungeractuator 2406. The viscous damper 2422 may use one or more viscousfluids, for example, silicon grease, to provide resistance. The viscousdamper 2422 may include a stationary housing holding a solid rotatingelement called a “rotor.” The outer circumference of the rotor mayinclude a plurality of teeth configured to be engaged by the teeth of agear in the gear train 2420. The rotor may be surrounded by a thin filmof a viscous fluid that is sealed inside the housing. The rotation ofthe rotor may provide resistance against the acceleration of the plungeractuator 2406 by shearing the viscous fluid. In an exemplary embodiment,the viscous damper 2422 may be replaced with a different viscous damperproviding a different level of damping.

The force required to turn the rotary viscous damper 2422 is describedwith reference to a coordinate system x where x=0 is at the free lengthof a spring. If m is the inertia of the system, c is the dampingcoefficient, and k is the spring constant, then:

$\begin{matrix}{{{m\overset{¨}{x}} + {c\overset{.}{x}} + {kx}} = { 0\Rightarrow\overset{¨}{x}  = {\frac{1}{m}\lbrack {{{- c}\overset{.}{x}} - {kx}} \rbrack}}} & (1) \\{{\overset{¨}{x} + {2{\zeta\omega}_{0}\overset{.}{x}} + {\omega_{0}^{2}x}} = 0} & (2)\end{matrix}$

where natural frequency:

$\begin{matrix}{\omega_{0} = \sqrt{\frac{k}{m}}} & (3)\end{matrix}$

and where damping ratio:

$\begin{matrix}{\zeta = \frac{c}{2\sqrt{mk}}} & (4)\end{matrix}$

If the damping is driven by a rotary damper, the torque T required toturn the dampener may be assumed to be linearly proportional to theangular velocity by some constant C:

T=C _(θ){dot over (θ)}  (5)

If the rotary damper is coupled to the plunger actuator by a gear trainof reduction N and a spool of diameter D, then:

$\begin{matrix}{{\overset{.}{x} = {{{\frac{D}{2N}\overset{.}{\theta}}\therefore\overset{.}{\theta}} = \frac{2N\overset{.}{x}}{D}}}{and}{T_{spool} = {\frac{F_{x}D}{2} = {{NT} = {{{NC}_{\theta}\overset{.}{\theta}} = {{{\frac{2N^{2}C_{\theta}}{D}\overset{.}{x}}\therefore F_{x}} = {{{\frac{4N^{2}C_{\theta}}{D^{2}}\overset{.}{x}}\therefore c_{x}} = \frac{4N^{2}C_{\theta}}{D^{2}}}}}}}}} & (6)\end{matrix}$

In another exemplary embodiment, an escapement may be used to resist theacceleration of the plunger actuator 2406. The escapement may use aknown period of oscillation of a balance wheel and a spiral hairspringto incrementally release the energy of a main spring. An escapement mayprovide a dependable design and linearity in the release of the energy.In another exemplary embodiment, a runaway escapement may be used toresist the acceleration of the plunger actuator 2406. In anotherexemplary embodiment, a swiss lever escapement may be used to resist theacceleration of the plunger actuator 2406.

A gear train 2420 may be provided for coupling the plunger actuator 2406to the regulating device 2422, i.e., the viscous damper or theescapement. The gear train 2420 may include a shaft 2424 may be coupledto the housing 2402 of the wearable automatic injection device 2400 witha close slip fit. In an exemplary embodiment, the shaft 2424 may supporta cylindrical structure 2426, for example, a spool or a shaft, and agear 2428 that is provided below the spool 2426. In an exemplaryembodiment, the spool 2426 may be a cam spool or a fusee. One or moresnap rings 2430 may be used to retain the spool 2426 and the gear 2428on the shaft 2424. The spool 2426 and the gear 2428 may be providedaround the shaft 2424 such that the centers of rotation of the spool2426 and the gear 2428 are aligned with each other and with the shaft2424. The spool 2426 and the gear 2428 may be cooperatively coupled toeach other and to the shaft 2424 such that the gear 2428 and the spool2426 may rotate together on the shaft 2424. In an exemplary embodiment,the spool 2426 and the gear 2428 may be taken off from the shaft 2424and replaced with a different set of spools and gears. The plungeractuator 2406 may be coupled to the gear train, for example, the spool2426, using one or more tethers or cables 2442.

In an exemplary embodiment, the spool 2426 may be any suitable rotatingmechanism including, but not limited to, a constant diameter spool, acam spool or fusee. If a cam or fusee is used, the outer diameter of thecam or fusee may vary with linear displacement D. Taking the equationfor the linear damping coefficient and holding the gear reduction N andthe rotary damping coefficient constant yields:

$\begin{matrix}{c_{x} = {\frac{4N^{2}C_{\theta}}{D^{2}} = \frac{a}{D_{x}^{2}}}} & (7)\end{matrix}$

where a is constant. Substituting the above into the equation of motionand assuming that the first derivative of χ is constant, yields:

$\begin{matrix}{D_{x} = {{\overset{¨}{\sqrt{\frac{{- a}\overset{.}{x}}{k}}}x^{- \frac{1}{2}}} = {{C_{1}x^{- b}} + C_{2}}}} & (8)\end{matrix}$

where C₁, C₂ and b are constants that may be varied in order to make thevelocity approximately constant. Plugging this variable into theequation of motion and solving for x as a function of time, x may besubstituted into equation (8) to determine D as a function of time,D_(t). The instantaneous velocity may be represented as:

$\begin{matrix}{\overset{.}{x} = { {\frac{D_{t}}{2}\overset{.}{\varphi}}\Rightarrow{\overset{.}{\varphi} - \frac{2\overset{.}{x}}{D_{t}}}\Rightarrow\varphi_{t}  = {\int\limits_{0}^{t}{\frac{2\overset{.}{x}}{D_{t}}{t}}}}} & (9)\end{matrix}$

where φ is the angular position of the cam or fusee. D_(t) and φ_(t) arethe polar coordinates of the cam profile.

Exemplary embodiments may couple the plunger actuator 2406 to a bung inthe barrel portion of a syringe or cartridge using any suitablemechanism. If a compression spring is used as the plunger actuator 2406,one or more tethers or cables may be used to couple the plunger actuator2406 to the bung. If a spiral spring is used as the plunger actuator2406, spur gearing may be used to couple the plunger actuator 2406 tothe bung. The torque generated the spiral spring by may be coupled tothe bung using a pinion to push a flexible rack around the corner of thesyringe or cartridge.

In an exemplary embodiment, the spool 2426 may be in contact with and/orcoupled to a ratchet 2434 and pawl 2436. A torsion spring (not pictured)may be provided below the pawl 2436 to preload the pawl 2436 against theratchet 2434. When the spool 2426 is being wound during assembly of thewearable automatic injection device 2400, the torsion spring may be heldin place. After the spool 2426 is wound and before an injection in apre-injection state, the ratchet 2434 and pawl 2436 may hold the spool2426 in place and prevent rotational movement of the spool 2426. Thisholds the tether 2442 in place which, in turn, maintains the plungeractuator 2406 in its compressed state, preventing movement of theplunger. At the beginning of an injection or during an injection in aninjection state, the pawl 2436 may be rotated to disengage the ratchet2434, for example, by a user or automatically upon the pressing of aninjection button. This allows the spool 2426 to rotate under the pullingforce of the tether 2442 caused by the spring force of the plungeractuator 2406. The spring force of the plunger actuator 2406 pulls thetether 2442 toward the distal end of the syringe or cartridge 2404.

One or more additional gears may be provided in contact with and/orcoupled to the gear coupled to the spool 2426, thus forming a gear train2438. Each gear in the gear train 2438 may be provided on acorresponding shaft coupled to the housing 2402 of the wearableautomatic injection device 2400. In an exemplary embodiment, the gearsin the gear train 2438 may be taken off from their corresponding shaftsand replaced with a different set of gears. One of ordinary skill in theart will recognize that other exemplary devices may include fewer ormore gears.

The gear train 2438 may be coupled to the viscous damper 2422 or anescapement that resists acceleration of the bung 2408. That is, the geartrain may couple the viscous damper 2422 or an escapement to the tether2442 holding the bung 2408 so that, when the bung 2408 is moved underthe force of the plunger actuator 2406, acceleration of the plungeractuator 2406 is resisted by the viscous damper 2422 or the escapement.

In an exemplary embodiment, the gear train 2438 may be coupled to anencoding device 2440, for example, a rotary encoder, that detects andlogs the angular displacement or position of the gear train and thecorresponding time. A computing device may be associated with thewearable automatic injection device to determine the position of thesyringe plunger based on the data obtained by the encoding device 2440.The computing device may also determine the flow rate of the therapeuticagent from the syringe or cartridge 2404 and the corresponding timebased on the data obtained by the encoding device 2440. The computingdevice may be provided integrally with the encoding device 2440 orseparately from the encoding device 2440. During assembly and testing ofthe wearable automatic injection device, the encoding device 2440 may beused to evaluate different gear trains, viscous dampers and biasingelements, validate mathematical models and account for variables notaddressed in the mathematical models. During use of the wearableautomatic injection device to perform an injection, the encoding device2440 may be used to indicate one or more conditions to the user, forexample, the flow rate of the therapeutic agent, malfunction of thedevice (for example, if the flow rate is too high or too low), and thelike.

In an exemplary embodiment illustrated in FIGS. 25 and 26, a wearableautomatic injection device may include a syringe assembly moveablerelative to a platform in the device. The wearable automatic injectiondevice includes a platform 2500, a slideable carriage 2502 coupled tothe platform 2500, and a syringe 2504 mounted on the slideable carriage2502. A distal end of the syringe 2504 may be coupled to a syringeneedle 2512. The syringe 2504 may include a barrel portion 2506containing a dose of a therapeutic agent sealed by a bung 2508. Aplunger actuator 2510 may be provided in the vicinity or in contact withthe bung 2508 for moving the bung 2508 forwardly within the barrelportion 2506. In an exemplary embodiment, the plunger actuator 2510 mayinclude a biasing mechanism coupled by a tether to a gear train andthereby to a damping mechanism.

The device may also include an injection button bearing an injectionneedle (not pictured) and including a pierceable septum that may bepierced by the syringe needle 2512. The septum may be coupled directlyor through a conduit to the injection needle such that, when pierced bythe syringe needle 2512, the septum establishes fluid communicationbetween the barrel portion 2506 and the injection needle.

In an exemplary embodiment, in a pre-injection state, the syringe needle2512 may already pierce the septum and be in fluid communication withthe injection needle. During an injection in an injection state, thedose of the therapeutic agent may be expelled from the barrel portion2506 when the plunger actuator 2510 is activated to move the bung 2508forwardly within the barrel portion 2506. In this embodiment, thecarriage 2502 may be stationary on the platform 2500.

In another exemplary embodiment, in a pre-injection state, the syringeneedle 2512 may be spaced from the septum and may not be in fluidcommunication with the injection needle. During an injection in aninjection state, the syringe 2504 may be moved forwardly within andrelative to the platform 2500 toward the septum in order to pierce theseptum with the syringe needle 2512. In this exemplary embodiment, thecarriage 2502 may be moveable and may move relative to the platform 2500toward the septum.

In an exemplary embodiment, a tether 2516 may be used to couple theplunger actuator 2510 to a gear train 2518. The gear train 2518 may inturn be coupled to a damping mechanism 2520 for providing a lineardelivery profile of the therapeutic agent. In a pre-injection state, alockout mechanism 2522 may hold the gear train 2518 in place and preventrotation of the gears. This causes the tether 2516 to hold the plungeractuator 2510 in place and prevents release of the plunger actuator2510, thereby preventing movement of the bung 2508. During an injectionin an injection state, the lockout mechanism 2522 may be released, forexample, manually by a user or automatically, thereby allowing the gears2518 to rotate under the biasing force of the plunger actuator 2510.This may allow the moveable carriage 2502 to automatically move towardthe septum, which results in the syringe needle 2512 piercing theseptum. The bung 2508 may also move within the barrel portion 2506toward the septum under the biasing force of the plunger actuator 2510to expel the dose through the syringe needle 2512.

FIGS. 27-29 illustrate a schematic of a portion of an exemplaryautomatic injection device that may include a syringe assembly that isstationary relative to the housing of the device. The wearable automaticinjection device 2800 includes a plunger actuation mechanism forautomatically actuating a bung 2802 in a barrel portion 2804. FIG. 27 isa top view through a cover of the device 2800. FIG. 28 is a side view ofthe device 2800. FIG. 29 is a perspective view through a cover of thedevice 2800.

The plunger actuation mechanism may include a biasing mechanism 2806that operates as the plunger actuator. In an exemplary embodiment, oneor more tethers or cables 2812 may be used to couple the biasingmechanism 2806 to a stage 3 gear 2810, for example a fusee, that unwindsto allow the biasing mechanism 2806 to expand. A stage 1 damper 2808,for example, a viscous damper or an escapement, regulates the movementof the bung 2802 during an injection in an injection state in order toachieve a linear flow rate of the therapeutic agent. One or more stage 2gears and pinions 2814 may be used to couple the stage 3 gear 2810 andthe stage 1 damper 2808.

Table 7 summarizes exemplary features of an exemplary stage 1 damper, anexemplary stage 2 gear, an exemplary stage 2 pinion and an exemplarystage 3 gear that may be used in exemplary automatic injection devices.

TABLE 7 Exemplary features of exemplary plunger actuation componentsStage 3 Gear Stage 2 Pinion Stage 2 Gear Stage 1 Damper Diametral 72teeth/in 72 teeth/in 31.75 teeth/in 31.75 teeth/in pitch Number of 50teeth 18 teeth 16 teeth 11 teeth teeth Face width 0.100 in 0.100 in0.050 in 0.118 in Tooth profile 14.5 deg 14.5 deg 14.5 deg 14.5 degMaterial Nylon Nylon Nylon Acetal Pitch diameter 0.694 in 0.250 in 0.504in 0.346 in Circular pitch 0.044 in/tooth 0.044 in/tooth 0.099 in/tooth0.099 in/tooth Yield strength 11.8 ksi 11.8 ksi 11.8 ksi 10.2 ksi Lewisform 0.346 0.270 0.255 0.192 factor Torque 8.5 oz-in 3.1 oz-in 3.1 oz-in2.1 oz-in Tangential 1.53 lbf 1.53 lbf 0.76 lbf 0.76 lbf force Radialforce 0.39 lbf 0.39 lbf 0.20 lbf 0.20 lbf Safety factor 3.71  2.90 6.25  9.62  Total gearing 4.04

Failure analysis was performed on the exemplary plunger actuationmechanism. In an exemplary embodiment, the gear train (including thestage 2 gear) is designed assuming a Lewis bending failure mode whichassumes that the gear tooth is a simple cantilever with tooth contactoccurring at the tip. The results of the failure analysis summarized inTable 7 indicate that the minimum factor of safety for the gear train is3 and that the total gear ratio is 4.04.

Different combinations of different types of plunger actuators (spring 1and spring 2), spools (constant-diameter spool or cam spool), anddamping mechanisms (viscous damper or escapement) were tested todetermine their effect on the delivery rate of the therapeutic agent.FIG. 30 illustrates x and y coordinates (in inches) of cam profiles for:(i) the combination of spring 1 and a viscous damper, (ii) thecombination of spring 1 and an escapement, (iii) the combination ofspring 2 and a viscous damper, and (iv) the combination of spring 2 andan escapement.

FIG. 31 illustrates a graph of therapeutic agent flow rates (inmilliliters per minute) versus time (in seconds) delivered by: (i) thecombination of spring 1 and a viscous damper, (ii) the combination ofspring 1, a viscous damper and a cam spool, (iii) the combination ofspring 1 and an escapement, (iv) the combination of spring 1, anescapement and a cam spool, (v) the combination of spring 2 and aviscous damper, (vi) the combination of spring 2, a viscous damper and acam spool, (vii) the combination of spring 2 and an escapement, (viii)the combination of spring 2, an escapement and a cam spool, and (ix) andan ideal flow rate in which the therapeutic agent is delivered at asubstantially constant rate. FIG. 32 illustrates a graph of the volumeof therapeutic agent (in milliliters) versus time (in seconds) deliveredby the combinations of components of FIG. 31.

FIGS. 31 and 32 show that a substantially linear flow rate of thetherapeutic agent may be achieved by the use of a cam spool or a fusee.The use of an escapement, versus a viscous damper, may be used toimprove the linearity of the flow rate. The total delivery time of thetherapeutic agent may be controlled by configuring the gearing ratio.

Different combinations of exemplary dampers and exemplary gear ratios inexemplary plunger actuation mechanisms were tested. The exemplarydampers included: (i) damping mechanism G, (ii) damping mechanism B,(iii) damping mechanism K, and (iv) damping mechanism V. The exemplarygear ratios included: (i) 4:1, (ii) 6.25:1, and (iii) 16:1. FIG. 33illustrates a graph of the volume of therapeutic agent (in milliliters)against time (in seconds) delivered using: (i) a G damping mechanismhaving a damping coefficient of about 10.3 lbf*s/in with a gear ratio of4:1, (ii) a B damping mechanism having a damping coefficient of about15.1 lbf*s/in with a gear ratio of 4:1, (iii) a K damping mechanismhaving a damping coefficient of about 18.9 lbf*s/in with a gear ratio of4:1, (iv) a V damping mechanism having a damping coefficient of about24.9 lbf*s/in with a gear ratio of 4:1, (v) a G damping mechanism havinga damping coefficient of about 25.1 lbf*s/in with a gear ratio of6.25:1, (vi) a B damping mechanism having a damping coefficient of about37.0 lbf*s/in with a gear ratio of 6.25:1, (vii) a K damping mechanismhaving a damping coefficient of about 46.2 lbf*s/in with a gear ratio of6.25:1, (viii) a V damping mechanism having a damping coefficient ofabout 60.7 lbf*s/in with a gear ratio of 6.25:1, (ix) a G dampingmechanism having a damping coefficient of about 164 lbf*s/in with a gearratio of 16:1, (x) a B damping mechanism having a damping coefficient ofabout 242 lbf*s/in with a gear ratio of 16:1, (xi) a K damping mechanismhaving a damping coefficient of about 303 lbf*s/in with a gear ratio of16:1, (xii) a V damping mechanism having a damping coefficient of about398 lbf*s/in with a gear ratio of 16:1, and (xiii) an ideal flow rate inwhich the therapeutic agent is delivered at a substantially constantrate.

FIG. 33 shows that increasing the damping coefficient for the same gearratio increases the delivery time of the same volume of therapeuticagent. In some cases, increasing the damping coefficient makes thedelivery rate more linear. For example, for the 6:25:1 gear ratio, thehighest damping coefficient of about 60.7 lbf*s/in yields lineardelivery rate than the lower damping coefficients.

FIG. 34 illustrates a graph of exemplary damper torques (that may beback-calculated from the displacement of the plunger actuator) againstdamper speeds (in rpm) for G, B, K and V model dampers having increasingdamping coefficients. The dots indicate the actual torque values and thedotted lines indicate the assumed manufacturer damping torque values,which indicates that the manufacturer values were underestimated. Thedata indicate that the torque values were substantially linear in therange of between 0 and about 20 rpm. This is evidenced by the highcorrelation coefficient for the linear fit equations shown in the graph.Using the new linear fit equations for the damper torque provided by thelinear fit adjusts the damping coefficient and includes a static torquevalue. Substituting these new values into a computer model allows for aclose approximation of the system response.

Since the static torque is multiplied by the gear ratio and subtractsdirectly from the spring force, it may be desirable to choose thehighest rate damper and the lowest gearing ratio in an exemplaryembodiment, for example, the V model damper and a 4:1 gearing ratio.FIG. 35 illustrates a graph of the volume of therapeutic agent (inmilliliters) against time (in seconds) delivered by different exemplarysyringes using a V model damper having a damping coefficient of about24.9 lbf*s/in and an exemplary gear ratio of 4:1.

After adjusting the computer models to reflect the measured dampertorque, a fusee was designed to linearize the delivery rate oftherapeutic agent. FIG. 36 illustrates a graph of the volume oftherapeutic agent (in milliliters) delivered and the diameter of thefusee or cam spool (in inches) versus the time (in seconds). Since thediameter of the fusee changes over the delivery, the angular positiondata was numerically integrated along the fusee curve to yield thelinear position data of the plunger actuator at each data point.

FIG. 36 shows that the actual measured delivery rate is about 10% slowerthan that predicted by the model but is nearly constant as evidenced bythe high correlation coefficient (0.9995). The discrepancy between themeasured and predicted data may be explained by inefficiencies in thegearing, for example, areas where the gearing binds may be seen as sharpchanges in slope in the graph. The discrepancy may also be explained bythe tether coupling the fusee to the plunger actuator not beingperfectly in line with the plunger actuator, or the spring rate of theplunger actuator being lower in reality than calculated. Regardless ofthe source of error, reducing the spring rate of the plunger actuator byabout 5% may produce a near perfect correlation (1.0).

Different exemplary damping mechanisms were tested at differenttemperatures to determine the effect of temperature on the dampingeffect, i.e., the linearity of the delivery of the therapeutic agent.The viscous rotary damping torque is dependent on the viscosity of thesilicon grease inside the rotary damper. The viscosity of the silicongrease depends in part on the temperature of the surroundingenvironment. Different exemplary damping mechanisms were also tested todetermine the effect of manufacturing variability in the dampingmechanisms on the damping effect, i.e., the linearity of the delivery ofthe therapeutic agent. Variations in damper manufacturing may affect theresisting torque provided by the damper.

FIG. 37 illustrates a graph of the volume of therapeutic agent (inmilliliters) delivered versus time (in seconds) achieved by: (i) a firstdamper at room temperature, (ii) the first damper at about 40 degreesFahrenheit (in a refrigerator), (iii) a second damper, (iv) the seconddamper at about 0 degree Fahrenheit (in a freezer), (v) a third damperhaving manufacturing variability relative to the first and seconddampers, and (vi) a fourth damper having manufacturing variabilityrelative to the first and second dampers.

FIG. 37 shows that changes in temperature did not substantially affectthe damping effect, i.e., the linearity of the delivery of thetherapeutic agent. However, the delivery rate was affected in some casesby decreasing the temperature, for example, for the first damper.Similarly, manufacturing variability in the damping mechanisms did notsubstantially affect the damping effect, i.e., the linearity of thedelivery of the therapeutic agent. However, the delivery rate wasaffected in some cases by manufacturing variability. The damper torquevalues varied by about 5% in the sample group tested.

Thus, one or more factors may be configured to control the linearityand/or the delivery rate of the therapeutic agent including, but notlimited to, the gear ratio, the damping coefficient, manufacturingdeviations in the damper, manufacturing deviations in the plungeractuator, and the like. In addition, other characteristics of theplunger actuator may be varied in order to control the linearity and/orthe rate of the flow of the therapeutic agent.

FIG. 38 illustrates a schematic of a portion of an exemplary automaticinjection device 2600 that employs a fusee and an escapement mechanism.The device 2600 includes a plunger actuation mechanism for automaticallyactuating a bung 2408 contained in a syringe or cartridge 2404. In theexemplary plunger actuation mechanism, a runaway escapement 2602 may beused to resist the acceleration of the plunger actuator 2406 byproviding linear damping. In the exemplary runaway escapement 2602, anescape wheel is provided having a plurality of teeth on itscircumferential periphery and a pallet is provided in the vicinity ofthe escape wheel. In an exemplary embodiment, the escape wheel may have30 teeth, although exemplary escape wheels are not limited to 30 teeth.The escape wheel may be coupled to the spool 2426 via one or more gearsforming a gear train. In an exemplary embodiment, a gearing ratio of50:1 may couple the spool 2426 to the escape wheel, but other exemplarygearing ratios may be used. The pallet may have an adjustable massmoment of inertia by way of pin holes that may be filed with one or morepins, for example, steel dowel pins.

In operation, when torque is applied to the escape wheel, the escapewheel rotates and a tooth of the escape wheel imparts an impulse torqueon the pallet such that the kinetic energy of the pallet is reversed.The tooth pushes aside an arm of the pallet. This causes the pallet tooscillate which frees the tooth of the escape wheel, simultaneouslybringing the alternate arm of the pallet into interference with a secondtooth of the escape wheel. As such, as the escape wheel rotates, itsmovement is arrested by periodic impact with the pallet, thus allowingthe escape wheel to rotate only when the pallet is free to oscillate. Asthe torque applied to the escape wheel increases, the escape wheelimparts a stronger impulse to the pallet, thus increasing theoscillation speed pallet and therefore allowing the escape wheel to movemore rapidly.

Assuming that the collisions between the teeth of the escape wheel andthe pallet are perfectly elastic, the pallet absorbs, for each impact:

T=J{dot over (φ)} ²

The power dissipation of the pallet is directly proportion to thefrequency of oscillation of the pallet w because two collisions occurbetween the escape wheel and the pallet for every oscillation of thepallet. Thus:

P=2ωJ{dot over (φ)} ²

Assuming an impulse time of zero, since the collisions are perfectlyelastic, the magnitude of the angular velocity {dot over (φ)} may beassumed to be constant and related to φ_(max), the angular distancebetween collisions (in radians) may be represented by:

{dot over (φ)}2ωφ_(max)

Thus,

P=8Jω ³φ_(max) ²

The rotational speed of the escape wheel {circumflex over (θ)} isrelated to the number of teeth n and the oscillation frequency ω and maybe represented as:

$\overset{.}{\theta} = { \frac{2{\pi\omega}}{n}\Rightarrow\omega  = \frac{n\; \overset{.}{\theta}}{2\pi}}$

Thus,

$P = \frac{J\; \phi_{\max}^{2}n^{3}{\overset{.}{\theta}}^{3}}{\pi^{3}}$

Since P=C_(θ){dot over (θ)}² for a viscous rotary damper:

$C_{\theta} = { \frac{J\; \phi_{\max}^{2}n^{3}{{\overset{.}{\theta}}^{3}}}{\pi^{3}}\Rightarrow F_{x}  = {{( \frac{2{nN}}{\pi \; D} )^{3}J\; \phi_{\max}^{2}{\overset{.}{x}}*\overset{.}{x}} = {C_{x}{\overset{.}{x}}*\overset{.}{x}}}}$

which creates a non-linear differential equation.

In another exemplary plunger actuation mechanism, a swiss leverescapement may be used to resist the acceleration of the plungeractuator. Assuming a coordinate system in which θ=0 is at theequilibrium of a coil spring attached to a balance wheel. If damping isnegligible in this system, then:

J{umlaut over (θ)}±kθ=0

Where k is the torsional spring constant of the coil spring and J is themass moment of inertia:

J=∫r ² dm

Where r is the distance from the center of rotation and m is mass, thenatural frequency of the system is:

$\omega_{0} = \sqrt{\frac{k}{J}}$

If the escapement wheel has n teeth and a spur gear train of speedreduction N couples the escapement to a spool of diameter D, then thespool rotates at angular velocity:

$\overset{.}{\varphi} = \frac{2{\pi\omega}_{0}}{nN}$

Taking the derivative of the equation relating θ to x:

$\frac{\;}{t}( {\varphi = \frac{2( {x - x_{0}} )}{D}} )$

which yields:

$\overset{.}{\varphi} = \frac{2\overset{.}{x}}{D}$

Thus,

$\overset{.}{x} = {\frac{\pi \; D\; \omega_{0}}{nN} = {\frac{\pi \; D}{nN}\sqrt{\frac{k}{J}}}}$

The components illustrated in FIG. 38 that are common to FIG. 24 aredescribed with reference to FIG. 24.

FIG. 39 illustrates an exemplary plunger actuation mechanism 3900 thatemploys one or more linear biasing mechanisms to provide a force forexpressing a therapeutic agent from the barrel portion 3902 of awearable automatic injection device. The barrel portion 3902 extendslongitudinally between a proximal end and a distal end, and isconfigured to hold a dose of a therapeutic agent. A distal end of thebarrel portion 3902 is coupled to a syringe needle 3904. A bung 3906 isprovided moveably within the barrel portion 3902 to seal the dose of thetherapeutic agent.

One or more linear springs 3908 are provided for providing a biasingforce upon the bung 3906 in order to move the bung 3906 within thebarrel portion 3902 toward the syringe needle 3904 during an injectionin an injection state. A distal end of the linear spring 3908 is in thevicinity of and/or in contact with a plunger 3916 having a plurality ofteeth configured for engagement with a damping mechanism. The plunger3916 may be provided in the vicinity of and/or in contact with a distalend of a force transmission mechanism, for example, one or more ballbearings 3910.

A distal end of the ball bearings 3910 may also be in the vicinity ofand/or in contact with the bung 3906 such that the biasing force of thespring 3908 is transmitted to the bung 3906 through the ball bearings3910. The ball bearings 3910 may be enclosed in an enclosed track 3912that restricts the lateral or sideway movement of the ball bearings3910. That is, the biasing force of the spring 3908 causes the plunger3916 and, in turn, ball bearings 3910 to move substantially in a back orforth manner, i.e., toward or away from the bung 3906. The use of theball bearings 3910 allows redirection of the biasing force to the bung3906 and allows minimization of the size of the device. When actuated,the spring 3908 exerts a biasing force in the direction of the bung3906. The biasing force is transmitted by the plunger 3916 and the ballbearings 3910 to the bung 3906 and causes the bung 3906 to move towardthe syringe needle 3904 within the barrel portion 3902. This causes thetherapeutic agent to be expressed through the syringe needle 3904 to theexterior of the barrel portion 3902.

A damping mechanism 3914, for example, a rotary viscous damper, may beprovided and associated with the spring 3908 and/or the plunger 3916 toregulate the rate of delivery of the therapeutic agent. The damper 3914may include a hub and a plurality of teeth that extend in a radialmanner about the hub. The teeth of the damper 3914 may be configured forengagement with the teeth of the plunger 3916. The damper 3914 mayprovide a force proportional to the speed of movement of the plunger3916 in order to regulate the delivery rate. As such, the exemplarysystem 3900 may be used to provide slow controlled delivery of thetherapeutic agent by configuring the force provided by the spring 3908and/or the properties of the damper 3914.

FIG. 40 illustrates an exemplary plunger actuation mechanism 4000 thatemploys one or more clock springs to provide a force to a bung in abarrel portion in order to expel a therapeutic agent from the barrelportion. A biasing means 4002 is provided by a compression helical coilspring characterized by spring coils of progressively increasingdiameter, such that when the spring is compressed, the coils nest onewithin the other in the manner of a clock spring, thereby taking up theminimum of space. A portion of the spring 4002 is in the vicinity ofand/or in contact with a mechanical escapement mechanism 4004 so thatthe rotary biasing force of the spring 4002 is converted into a lineardisplacement of the mechanical escapement mechanism 4004. The mechanicalescapement mechanism 4004 may be in the vicinity of and/or in contactwith the bung such that the biasing force of the spring 4002 istransmitted as a linear displacement to the bung through the motion ofthe mechanical escapement mechanism 4004. That is, the biasing force ofthe spring 4002 causes the mechanical escapement mechanism 4004 to movesubstantially in a back or forth manner, i.e., toward or away from thebung. The use of the mechanical escapement mechanism 4004 allowsredirection of the biasing force to the bung and allows minimization ofthe size of the device.

When actuated, the spring 4002 exerts a biasing force that is convertedto a back and forth force by the mechanical escapement mechanism 4004 inthe direction of the bung. The biasing force is transmitted directly orindirectly to the bung and causes the bung to move toward the needlewithin the barrel portion. This causes the therapeutic agent to beexpressed through the needle to the exterior of the barrel portion. Assuch, the exemplary system 4000 may be used to provide slow controlleddelivery of the therapeutic agent by configuring the force provided bythe spring 4002 and/or the linear displacement provided by themechanical escapement mechanism 4004. The mechanical escapementmechanism 4004 may be configured to control, for example, the amount ofadvance per cycle. The spring 4002 may be sized to predominate overstick-slip forces.

FIGS. 41 and 42 illustrate an exemplary automatic injection device 4100that employs a fluid-based plunger actuation mechanism in which thefluid pressure and/or movement of a working fluid is used to move a bungwithin the barrel portion of a syringe or cartridge. The plungeractuation mechanism includes one or more fluid circuits to provide aforce to a bung for expressing a dose of a therapeutic agent from abarrel portion 4104 of a syringe or cartridge. FIG. 41 is a schematic ofthe exemplary automatic injection device 4100 and FIG. 40 is aperspective view of the exemplary automatic injection device 4100. Thewearable automatic injection device 4100 may include a pressure element4106 that stores an incompressible working fluid that provides a fluidpressure. Exemplary working fluids may include, but are not limited to,water, air, oil, and the like. Exemplary pressure elements 4106 mayinclude, but are not limited to, an elastic bladder, a master cylinder,a spring-loaded syringe, and the like.

The pressure element 4106 may be coupled to a flow restrictor 4108 via atubing 4110. The flow restrictor 4108 may restrict the flow of theworking fluid so that the fluid pressure upstream of the flow restrictoris greater than the fluid pressure downstream of the flow restrictor.The flow restrictor 4108 may include an orifice of diameter ranging fromabout 0.001 inch to about 0.01 inch, but the diameters of exemplary flowrestrictor orifices are not limited to this exemplary range. The orificeof the flow restrictor 4108 may have lengths ranging from about 10 mm toabout 50 mm, but the lengths of exemplary flow restrictor orifices arenot limited this exemplary range.

Exemplary embodiments may configure a number of characteristics of thedelivery system to control the total delivery time of the therapeuticagent. Exemplary embodiments may also configure a number ofcharacteristics of the delivery system based on the viscosity of theworking fluid and/or the therapeutic agent. Exemplary characteristicsmay include, but are not limited to, the diameter of the orifice, thelength of the orifice, the viscosity of the working fluid, and the like.For example, the diameter of the orifice of the flow restrictor may bedecreased to increase the total delivery time.

The flow restrictor 4108 may also be coupled to the bung via a tubing4112. When the working fluid is released from the pressure element 4106via the flow restrictor 4108, the fluid pressure of the working fluiddrives the bung forwardly within the barrel portion 4104 in order toexpel the dose of the therapeutic agent from the barrel portion 4104.

In an exemplary embodiment, before an injection in a pre-injectionstate, the working fluid may not be released from the pressure element4106. In this exemplary embodiment, a delivery trigger (not pictured)may be coupled to the pressure element 4106 so that, upon activation ofthe delivery trigger, the working fluid is released from the pressureelement 4106 into the tubings 4110 and 4112. The fluid pressure of theworking fluid advances the bung within the barrel portion 4104, thusinjecting the dose into the patient's skin. Thus, the fluid circuitestablished by the flow of the working fluid and the flow restrictor mayprovide a regulated force to the bung.

In an exemplary embodiment, the dose is delivered in a linear deliveryprofile, i.e., at a substantially constant delivery rate. Linearity ofthe delivery profile may be achieved by the high pressure of the workingfluid provided by the pressure element 4106 upstream of the flowrestrictor 4108 and the damping effect provided by the flow restrictor4108. The pressure upstream of the flow restrictor 4108 may bemaintained at a high level relative to projected stick-slip forces suchthat a highly damped system is achieved. For the bung to be movedforward within the barrel portion 4104, the bung would need to pull avacuum on the working fluid between the flow restrictor 4108 and thebarrel portion 4104, which is difficult to achieve to an appreciableextent because the working fluid is essentially incompressible.

Exemplary damped hydraulic delivery circuits allow movement of the bungvia volumetric metering, rather than by a direct application of force,thereby minimizing stick-slip phenomena in the delivery profile of thetherapeutic agent.

In an exemplary embodiment, an exemplary volume of 0.8 milliliters oftherapeutic agent may be delivered at an exemplary delivery pressure ofabout 16.5 psi within an exemplary duration of about 12 minutes. Inanother exemplary embodiment, an exemplary volume of 0.8 milliliters oftherapeutic agent may be delivered at an exemplary delivery pressure ofabout 5 psi within an exemplary duration of about 17 minutes.

FIG. 43 illustrates a graph of the cumulative amount of therapeuticagent (in grams) against time (in seconds) as delivered by an exemplarydelivery system at an exemplary delivery pressure of about 16.5 psi.FIG. 44 illustrates a graph of the cumulative volume of therapeuticagent (in milliliters) against time (in seconds) as delivered by anexemplary delivery system including a first exemplary flow restrictorhaving an exemplary diameter of about 0.008 inches and an exemplarylength of about 34.3 mm. The total delivery time for delivering about 1milliliters of a therapeutic agent was about twenty seconds. FIG. 45illustrates a graph of the cumulative volume of therapeutic agent (inmilliliters) against time (in seconds) as delivered by an exemplarydelivery system including a second exemplary flow restrictor having anexemplary diameter of about 0.002 inches and an exemplary length ofabout 34.3 mm. The total delivery time for delivering about 1milliliters of a therapeutic agent was about 15 minutes. In theillustrative graphs, the delivery profile is substantially linear, i.e.,substantially constant over time, and does not display an initial bolusor abrupt changes or inflections representative of inconsistent deliveryrates.

FIG. 46 is a schematic drawing of an exemplary automatic injectiondevice 4600 that employs one or more fluid circuits to provide a forcefor expressing a therapeutic agent from a cartridge assembly. FIG. 47 isa top view of the exemplary device 4600. The exemplary automaticinjection device 4600 includes a barrel portion 4602 containing a doseof a therapeutic agent. A distal end of the barrel portion 4602 isprovided in the vicinity of or coupled to a syringe needle (hidden by aneedle cover 4604) that is protectively covered by a needle cover 4604.The device 4600 includes an injection button that includes a septum andbears an injection needle (not pictured). In an exemplary embodiment,the device 4600 may include an injection needle carrier 4606 for holdingthe injection needle. In an exemplary embodiment, the injection needlemay be extend substantially orthogonally to the plane of the device asillustrated, and may be held in place by the needle carrier 4606. Aneedle lock 4608 may be provided for preventing the injection needlefrom exiting the housing once engaged and may be located in the housingnear the injection needle.

In an exemplary embodiment, a syringe or cartridge actuator 4610 may beprovided for advancing the barrel portion 4602 within the housing towardthe septum. A trigger may be provided for triggering the syringe orcartridge actuator 4610, for example, when the injection button ispressed down or when the needle cover 4604 is removed.

In this exemplary embodiment, a master cylinder 4612 containing aworking fluid is provided for providing a fluid pressure to actuate abung 4614 within the barrel portion 4602. The master cylinder 4612 maybe coupled to a delivery trigger 4616 that, when activated, releases theworking fluid into fluid communication with the bung 4614 and allows thefluid pressure to advance the bung 4614 within the barrel portion 4602.

Exemplary embodiments also provide needle retraction systems forretracting an injection needle from a vertically lowered position (or anextended or deployed position) outside the housing of the device at thepatient contact region to a vertically raised position (or a retractedposition) within the housing of the device. The wearable automaticinjection device 4600 includes a retraction mechanism that automaticallyraises the injection button from a vertically depressed position withinthe housing during an injection in an injection state to a verticallyraised position within the housing in a post-injection state after aninjection. In an exemplary embodiment, the retraction mechanism may be atelescoping element. The master cylinder 4612 may be coupled to aretraction trigger that, when activated, releases the working fluid intofluid communication with the retraction trigger and allows the fluidpressure to activate the retraction mechanism.

FIG. 48 illustrates a top view of the device 4600 which shows a conduit4802 coupling the master cylinder 4612 to a flow restrictor 4804, aconduit 4806 coupling the flow restrictor 4804 to the bung in the barrelportion of the device, and a conduit 4808 coupling the master cylinder4612 to a retraction mechanism 4810 via a valve 4812, for example, acheck valve. FIG. 49 illustrates a schematic diagram of the device 4600.

The check valve 4812 may have a suitable cracking pressure at or abovewhich the check valve 4812 allows fluid into the conduit 4808 coupled tothe retraction mechanism 4810. In an exemplary embodiment, the crackingpressure is higher than the maximum fluid pressure in the conduit 4806required to drive the bung during an injection in an injection state.Otherwise, undesirably, the needle retraction process may begin duringor even before the injection. In an exemplary embodiment, the pressurein the conduit 4806 at the end of the movement of the bung during aninjection in an injection state is higher than the cracking pressure.Otherwise, at the end of the movement of the bung, the pressure in theconduit 4808 may be insufficient to activate the retraction mechanism4810. The volume of the working fluid in the master cylinder 4612 issufficient to deliver the entire dose of the therapeutic agent and toactivate the retraction mechanism 4810.

In an exemplary embodiment, the retraction mechanism 4810 and the checkvalve 4812 may be provided separately. In another exemplary embodiment,the retraction mechanism 4810 and the check valve 4812 may be providedas a single element, for example, as an inverting diaphragm.

FIG. 50 illustrates a graph of the pressure after the check valve andbehind the bung (in psi) versus time (in seconds) in an exemplaryembodiment. In an exemplary embodiment, the cracking pressure of thecheck valve may be about 7.5 psi and the diameter of the flow restrictororifice may be about 0.008 inches.

During an injection in an injection state, the flow restrictor 4804 maycause the pressure in the conduit 4802 to be about 10 to about 15 psi,while the pressure in the conduit 4806 may be about 5 to about 6 psi.The check valve 4812 thus prevents any flow of the working fluid fromentering the conduit 4808 while the bung is moving during the injection.Once the bung stops moving at the end of the injection, i.e., when thedose has been completely expelled from the barrel portion, the pressurein the conduit 4806 increases beyond 7.5 psi. This causes the checkvalve 4812 to open, allowing the working fluid to flow into the conduit4808 which activates the retraction mechanism 4810. The retractionmechanism 4810 in turn unlocks the needle lock and retracts theinjection button/carrier 4606 bearing the injection needle. Because itis based on pressure equalization in the hydraulic circuit, the needleretraction process ensures that the entire dose is delivered before theinjection needle is retracted, maximizes utilization of the therapeuticagent, and minimizes the overfill required in the barrel portion 4602.

Any suitable trigger mechanism may be used to trigger the needleretraction systems. In an exemplary embodiment, the trigger mechanismmay automatically trigger the needle retraction system when the wearableautomatic injection device moves from an injection state to apost-injection state. In an exemplary embodiment, completion of thedelivery of a therapeutically effective dose of the therapeutic agentmay trigger the needle retraction system. In another exemplaryembodiment, the removal of the device from the patient before completionof the delivery of a therapeutically effective dose of the therapeuticagent may trigger the needle retraction system. In another exemplaryembodiment, the needle retraction system may be manually triggered by auser.

FIG. 51 illustrates a side view of an exemplary automatic injectiondevice 5100 in which the housing 5102 of the wearable automaticinjection device 5100 includes a skin sensor foot 5104, which is astructure in an exemplary embodiment housed under or in the portion ofthe housing 5102 proximal to the injection site. In an exemplaryembodiment, prior to injection of the therapeutic agent and duringinjection, the skin sensor foot 5104 is retained within or forms aportion of the underside of the housing 5102. When the wearableautomatic injection device 5100 is attached to the injection site andactivated, the skin sensor foot 5104 may be free to move but may beconstrained by the injection site. In an exemplary embodiment, when thewearable automatic injection device 5100 is removed from the injectionsite, regardless of whether the drug delivery was completed, the skinsensor foot 5104 is no longer constrained, and extends and projectsoutside the periphery of the housing 5102. This, in turn, trips aretraction trigger. When the retraction trigger is activated, aretraction mechanism retracts the injection needle which may also raisethe injection button from the vertically lowered position to thevertically raised position, so that the injection button protrudes fromthe top of the housing 5102 and the injection needle is retracted withinthe housing 5102.

V. EXEMPLARY NEEDLE PROTECTION SYSTEMS

Exemplary embodiments provide different exemplary needle protectionsystems for maintaining the injection needle within the wearableautomatic injection device in a post-injection state after an injection.Protection of the needle prevents accidental needle sticks from injuringthe patient or any other humans in the vicinity of the wearableautomatic injection device.

FIGS. 52A and 52B illustrate an exemplary needle protection system 5200that maintains an injection needle 5202 in a retracted position within ahousing 5204 of an automatic injection system. The injection needle 5202is movable relative to the housing 5204 away from or toward thepatient's skin. When the needle 5202 is in a position within the housing5204 farther from the patient's skin, the needle 5202 is in a retractedposition and does not protrude outside the housing 5204. When the needle5202 is in a position within the housing 5204 closer to the patient'sskin, the needle 5202 is in an inserted or deployed position andprotrudes fully or partly from the housing 5204. The housing 5204 may beprovided with an aperture 5206 through which the needle 5202 mayprotrude outside the housing 5204.

The needle protection system 5200 employs a barrier mechanism 5208 whichprevents the needle 5202 from protruding from the housing 5204 in apre-injection state before an injection and in a post-injection stateafter an injection when the needle 5202 is in the retracted position.FIG. 52A illustrates the system 5200 in which the needle 5202 is in aninserted or deployed position and protrudes fully or partly through theaperture 5206 outside the housing 5204, for example, during an injectionin an injection state. In this case, the barrier mechanism 5208 isdisplaced away from the aperture 5206 so that the aperture 5206 is opento the outside of the housing 5204, and the needle 5202 is free toprotrude through the aperture 5206 to the outside of the housing 5204.FIG. 52B illustrates the system 5200 in which the needle 5202 is in aretracted position and does not protrude from the housing 5204, forexample, in a pre-injection state and a post-injection state. In thiscase, the barrier mechanism 5208 is aligned with and covers the aperture5206 so that the aperture 5206 is no longer open to the outside of thehousing 5204, and the needle 5202 is not free to protrude through theaperture 5206 to the outside of the housing 5204. In an exemplaryembodiment, the barrier mechanism 5208 may be moved rotatably above apoint of rotation between a first position in which it exposes theaperture 5206 (in FIG. 52A) to a second position in which it covers theaperture 5206 (in FIG. 52B).

FIGS. 53A and 53B illustrate another exemplary needle protection system5300 provided in the housing 5302 of an automatic injection system. Theautomatic injection system includes an injection needle 5304 that ismovable relative to the housing 5302 away from or toward the patient'sskin. When the needle 5304 is in a position within the housing 5302farther from the patient's skin, the needle 5304 is in a retractedposition and does not protrude outside the housing 5302. When the needle5304 is in a position within the housing 5302 closer to the patient'sskin, the needle 5304 is in an inserted or deployed position andprotrudes fully or partly from the housing 5302.

The needle protection system 5300 includes a needle lockout sleeve 5306provided in the vicinity of the injection needle 5304 for locking theinjection needle in the retracted position in a pre-injection state anda post-injection state. The needle lockout sleeve 5306 may be coupled toa pin 5308 disposed in a slot 5310. The pin 5308 may be in a firstposition (illustrated in FIG. 53A) relative to the slot 5310 in whichthe needle lockout sleeve 5306 locks the injection needle 5304 in theretracted position within the housing 5302. The pin 5308 may be in asecond position (illustrated in FIG. 53B) relative to the slot 5310 inwhich the needle lockout sleeve 5306 allows the injection needle 5304 toprotrude outside the housing 5302.

In an exemplary embodiment, an early-removal retraction trigger 5312that, when tripped, triggers a retraction mechanism that retracts theinjection needle 5304 into the housing 5302. The early-removalretraction trigger 5312 may be tripped when the wearable automaticinjection device 5300 is removed from the injection site before thetherapeutically effective dose of therapeutic agent is completelydelivered. In an exemplary embodiment, the early-removal retractiontrigger 5312 may include a latch 5314, e.g., a flexible plastic hook,that is released upon removal of the wearable automatic injection device5300 from the injection site. FIG. 53A shows the early-removalretraction trigger 5312 in which the latch 5314 is engaged to a portionof the lockout sleeve 5306 when the wearable injection device is coupledto the injection site. FIG. 53B shows the early-removal retractiontrigger 5312 in which the latch 5314 is released from the portion of thelockout sleeve 5306 when the wearable injection device is removed fromthe injection device. Release of the latch 5314 from the portion of thelockout sleeve 5306 triggers the retraction mechanism. An exemplaryretraction mechanism may be responsive to an end-of-dose retractiontrigger and responsive to the early-removal retraction trigger 5310 toautomatically retract the injection needle 5304 from the injection site.

FIG. 54 illustrates an exemplary needle protection system 5400 thatmaintains an injection needle held by an injection carrier 5402 in aretracted position within a housing 5404 of an automatic injectionsystem. The injection needle is movable relative to the housing 5404away from or toward the patient's skin. When the injection needle is ina position within the housing 5404 farther from the patient's skin, theneedle is in a retracted position and does not protrude outside thehousing 5404. When the needle is in a position within the housing 5404closer to the patient's skin, the needle is in an inserted or deployedposition and protrudes fully or partly from the housing 5404. Thehousing 5404 may be provided with an aperture through which the needlemay protrude outside the housing 5404.

The needle protection system 5400 includes a needle lock 5408 providedin the vicinity of or in contact with the needle carrier 5402. In anexemplary embodiment, the needle lock 5408 may be a pivoting or rotatingmember that may pivot or rotate about a pivoting point or interface. Aneedle lock release mechanism 5410 may be provided in the vicinity of orin contact with the needle lock 5408. The needle lock release mechanism5410 may be in a first position when the injection needle is in avertically lowered position and protrudes outside the housing 5404 (inan injection state), and in a second position when the injection needleis in a vertically raised or retracted position within the housing 5404(in a pre-injection state or a post-injection state)

When the needle lock release mechanism 5410 is in the first position(that is, when the injection needle is in a vertically lowered injectionposition), the needle lock 5408 may be in an unlocked position in whichit does not lock the injection needle in the vertically raised positionin the housing 5404. Alternatively, the needle lock 5408 may in a lockedposition in which it locks the injection needle 5408 in the verticallylowered position in the housing 5404. In an exemplary embodiment (thatis, when the injection needle is in a vertically lowered injectionposition), retraction of the injection needle and/or the needle carrier5402 to the vertically raised position within the housing 5404 maytrigger the needle lock release mechanism 5410, i.e., move the releasemechanism from the first position to the second position. When theneedle lock release mechanism 5410 is moved to the second position, theneedle lock 5408 may pivot or rotate, thereby locking the injectionneedle and/or the needle carrier 5402 in the vertically raised positionin the housing 5404.

FIG. 55 illustrates an exemplary needle protection system 5500 thatmaintains an injection needle held by an injection carrier 5502 in aretracted position within a housing 5504 of an automatic injectionsystem. The injection needle is movable relative to the housing 5504away from or toward the patient's skin. When the injection needle is ina position within the housing 5504 farther from the patient's skin, theneedle is in a retracted position and does not protrude outside thehousing 5504. When the needle is in a position within the housing 5504closer to the patient's skin, the needle is in an inserted or deployedposition and protrudes fully or partly from the housing 5504. Thehousing 5504 may be provided with an aperture through which the needlemay protrude outside the housing 5504.

The needle protection system 5500 includes a needle lock 5508 providedin the vicinity of or in contact with the needle carrier 5502. In anexemplary embodiment, the needle lock 5508 may be a pivoting or rotatingmember that may pivot or rotate about a pivoting point or interface. Theneedle lock 5508 may include a biasing mechanism 5506 that applies arotational spring force to the needle carrier 5502 about a longitudinalaxis of the biasing mechanism. In an exemplary embodiment, the needlelock 5508 may be provided in a symmetrical manner about the needlecarrier 5502 such that the rotational force is applied by the biasingmechanism 5506 substantially symmetrically about the needle carrier5502.

A needle lock release mechanism 5510 may be provided in the vicinity ofor in contact with the needle lock 5508. The needle lock releasemechanism 5510 may be in a first position when the injection needle isin a vertically lowered position and protrudes outside the housing 5504(in an injection state), and in a second position when the injectionneedle is in a vertically raised or retracted position within thehousing 5504 (in a pre-injection state or a post-injection state)

When the needle lock release mechanism 5510 is in the first position(that is, when the injection needle is in a vertically lowered injectionposition), the biasing mechanism 5506 may apply a spring force to theneedle carrier 5502 in the clockwise direction toward the patient's bodysuch that the needle carrier 5502 is held in the vertically loweredposition. When the needle lock release mechanism 5510 is in the secondposition (that is, when the injection needle is in a vertically raisedpre or post-injection state), the biasing mechanism 5506 may apply aspring force to the needle carrier 5502 in the counter-clockwisedirection away from the patient's body such that the needle carrier 5502is raised to and held in the vertically raised position.

In an exemplary embodiment, retraction of the injection needle and/orthe needle carrier 5502 to the vertically raised position within thehousing 5504 may trigger the needle lock release mechanism 5510, i.e.,move the release mechanism from the first position to the secondposition. When the needle lock release mechanism 5510 is moved to thesecond position, the needle lock 5508 may pivot or rotate under theforce of the biasing member 5506 in the counter-clockwise direction awayfrom the patient's body, thereby locking the injection needle and/or theneedle carrier 5502 in the vertically raised position in the housing5504.

VI. THERAPEUTIC AGENTS FOR USE IN EXEMPLARY AUTOMATIC INJECTION DEVICES

Exemplary automatic injection devices may be used to administeressentially any substance or therapeutic agent that is suitable foradministration by injection. Typically, the substance or therapeuticagent will be in a fluid, e.g., liquid form, although medications inother forms such as gels or semi-solids, slurries, particulatesolutions, etc. also may suitable for use if the wearable automaticinjection device is designed to permit the administration of such formsof the medication.

Preferred medications are biological agents, such as antibodies,cytokines, vaccines, fusion proteins and growth factors. Methods ofmaking antibodies are described above.

Non-limiting examples of other biological agents that can be used as themedication in the automatic injection device include but are not limitedto antibodies to or antagonists of human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-15, IL-16, IL-18, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF,and PDGF; antibodies to cell surface molecules such as CD2, CD3, CD4,CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90,CTLA or their ligands including CD154 (gp39 or CD40L); TNFα convertingenzyme (TACE) inhibitors; IL-1 inhibitors (Interleukin-1-convertingenzyme inhibitors, IL-1RA etc.); Interleukin 11; IL-18 antagonistsincluding IL-18 antibodies or soluble IL-18 receptors, or IL-18 bindingproteins; non-depleting anti-CD4 inhibitors; antagonists of theco-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies,soluble receptors or antagonistic ligands; agents which interfere withsignaling by proinflammatory cytokines such as TNFα or IL-1 (e.g. IRAK,NIK, IKK, p38 or MAP kinase inhibitors); IL-1 □ converting enzyme (ICE)inhibitors; T-cell signaling inhibitors such as kinase inhibitors;metalloproteinase inhibitors; angiotensin converting enzyme inhibitors;soluble cytokine receptors and derivatives thereof (e.g. soluble p55 orp75 TNF receptors and the derivatives p75TNFRIgG (Enbrel™ and p55TNFRIgG(Lenercept)), sIL-1RI, sIL-1RII, sIL-6R); antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGF-beta); Rituximab; IL-1 TRAP;MRA; CTLA4-Ig; IL-18 BP; anti-IL-18; anti-IL15; IDEC-CE9.1/SB 210396(non-depleting primatized anti-CD4 antibody; IDEC/SmithKline; see e.g.,Arthritis & Rheumatism (1995) Vol. 38; S185); DAB 486-IL-2 and/or DAB389-IL-2 (IL-2 fusion proteins; Seragen; see e.g., Arthritis &Rheumatism (1993) Vol. 36; 1223); Anti-Tac (humanized anti-IL-2Ra;Protein Design Labs/Roche); IL-4 (anti-inflammatory cytokine;DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatorycytokine; DNAX/Schering); IL-10 and/or IL-4 agonists (e.g., agonistantibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra(Kineret®/Amgen); TNF-bp/s-TNF (soluble TNF binding protein; see e.g.,Arthritis & Rheumatism (1996) 39(9, supplement); 5284; Amer. J.Physiol.—Heart and Circulatory Physiology (1995) 268:37-42); R973401(phosphodiesterase Type IV inhibitor; see e.g., Arthritis & Rheumatism(1996) 39(9, supplement); S282); MK-966 (COX-2 Inhibitor; see e.g.,Arthritis & Rheumatism (1996) 39(9, supplement); S81); Iloprost (seee.g., Arthritis & Rheumatism (1996) 39(9, supplement); S82); zap-70and/or lck inhibitor (inhibitor of the tyrosine kinase zap-70 or lck);VEGF inhibitor and/or VEGF-R inhibitor (inhibitors of vascularendothelial cell growth factor or vascular endothelial cell growthfactor receptor; inhibitors of angiogenesis); TNF-convertase inhibitors;anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11 (see e.g.,Arthritis & Rheumatism (1996) 39(9, supplement), S296); interleukin-13(see e.g., Arthritis & Rheumatism (1996) 39(9, supplement), S308);interleukin-17 inhibitors (see e.g., Arthritis & Rheumatism (1996) 39(9,supplement), S120); anti-thymocyte globulin; anti-CD4 antibodies;CD5-toxins; ICAM-1 antisense phosphorothioate oligo-deoxynucleotides(ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1(TP10; T Cell Sciences, Inc.); and anti-IL2R antibodies.

VII. TNFα INHIBITORS FOR USE IN EXEMPLARY AUTOMATIC INJECTION DEVICES

According to one embodiment of the invention, the illustrative automaticinjection device may be used to deliver a dose of a TNF inhibitor usedto treat arthritis and other diseases. In one embodiment, the solutioncontained in the syringe contains 40 or 80 milligrams of drug product(TNFα blocker or inhibitor)/1 mL, for example, 40 or 80 mg adalimumab,4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dehydrate,1.22 mg dibasic sodium phosphate dehydrate, 0.24 mg sodium citrate, 1.04mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 50 andwater for injection, with USP sodium hydroxide added as necessary toadjust pH to be about 5.2.

The present invention can be used to administer a dose of a substance,such as a liquid drug, e.g., a TNFα inhibitor, to a patient. In oneembodiment, the dose delivered by the automatic injection device of theinvention comprises a human TNFα antibody, or antigen-binding portionthereof.

In one embodiment, the TNF inhibitor used in the methods andcompositions of the invention includes isolated human antibodies, orantigen-binding portions thereof, that bind to human TNFα with highaffinity and a low off rate, and have a high neutralizing capacity.Preferably, the human antibodies of the invention are recombinant,neutralizing human anti-hTNFα antibodies, such as, e.g., therecombinant, neutralizing antibody referred to as D2E7, also referred toas HUMIRA^(□) or adalimumab (Abbott Laboratories; the amino acidsequence of the D2E7 VL region is shown in SEQ ID NO: 1 of U.S. Pat. No.6,090,382 the amino acid sequence of the D2E7 VH region is shown in SEQID NO: 2 of U.S. Pat. No. 6,090,382). Properties of D2E7 have beendescribed in Salfeld et al., U.S. Pat. Nos. 6,090,382, 6,258,562, and6,509,015. Other examples of TNFα inhibitors include chimeric andhumanized murine anti-hTNFα antibodies that have undergone clinicaltesting for treatment of rheumatoid arthritis (see e.g., Elliott et al.(1994) Lancet 344:1125-1127; Elliot et al. (1994) Lancet 344:1105-1110;and Rankin et al. (1995) Br. J. Rheumatol. 34:334-342).

An anti-TNFα antibody (also referred to herein as a TNFα antibody), oran antigen-binding fragment thereof, includes chimeric, humanized, andhuman antibodies. Examples of TNFα antibodies that may be used in theinvention include, but not limited to, infliximab (Remicade®, Johnsonand Johnson; described in U.S. Pat. No. 5,656,272, incorporated byreference herein), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibodyfragment), an anti-TNF dAb (Peptech), and CNTO 148 (golimumab; Medarexand Centocor, see WO 02/12502). Additional TNF antibodies that may beused in the invention are described in U.S. Pat. Nos. 6,593,458;6,498,237; 6,451,983; and 6,448,380.

Other examples of TNFα inhibitors which may be used in the methods andcompositions of the invention include etanercept (Enbrel, described inWO 91/03553 and WO 09/406476), soluble TNF receptor Type I, a pegylatedsoluble TNF receptor Type I (PEGs TNF-R1), p55TNFR1gG (Lenercept), andrecombinant TNF binding protein (r-TBP-I) (Serono).

In one embodiment, exemplary embodiments provide improved uses andcompositions for treating a disorder in which TNFα is detrimental, e.g.,rheumatoid arthritis, with a TNFα inhibitor, e.g., a human TNFαantibody, or an antigen-binding portion thereof, through a wearableautomatic injection device.

A TNFα inhibitor includes any agent (or substance) that interferes withTNFα activity. In a preferred embodiment, the TNFα inhibitor canneutralize TNFα activity, particularly detrimental TNFα activity whichis associated with disorders in which TNFα activity is detrimental,including, but not limited to, rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondylitis, Crohn's disease, psoriasis, andpsoriatic arthritis.

VIII. PHARMACEUTICAL COMPOSITIONS FOR USE IN EXEMPLARY AUTOMATICINJECTION DEVICES

Pharmaceutical compositions may be loaded into the automatic injectiondevice of the invention for delivery to a patient. In one embodiment,antibodies, antibody-portions, as well as other TNFα inhibitors, can beincorporated into pharmaceutical compositions suitable foradministration to a patient using the device of the invention.Typically, the pharmaceutical composition comprises an antibody,antibody portion, or other TNFα inhibitor, and a pharmaceuticallyacceptable carrier. “Pharmaceutically acceptable carrier” includes anyand all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and the likethat are physiologically compatible. Examples of pharmaceuticallyacceptable carriers include one or more of water, saline, phosphatebuffered saline, dextrose, glycerol, ethanol and the like, as well ascombinations thereof. In many cases, it is preferable to includeisotonic agents, for example, sugars, polyalcohols such as mannitol,sorbitol, or sodium chloride in the composition. Pharmaceuticallyacceptable carriers may further comprise minor amounts of auxiliarysubstances such as wetting or emulsifying agents, preservatives orbuffers, which enhance the shelf life or effectiveness of the antibody,antibody portion, or other TNFα inhibitor.

The compositions for use in the methods and compositions of theinvention may be in a variety of forms in accordance with administrationvia the device of the invention, including, for example, liquidsolutions (e.g., injectable and infusible solutions), dispersions orsuspensions. In a preferred embodiment, the antibody or other TNFαinhibitor is administered by subcutaneous injection using the device ofthe invention. In one embodiment, the patient administers the TNFαinhibitor, including, but not limited to, TNFα antibody, orantigen-binding portion thereof, to himself/herself using the device ofthe invention

Therapeutic compositions typically must be sterile and stable under theconditions of manufacture and storage. The composition can be formulatedas a solution, microemulsion, dispersion, liposome, or other orderedstructure suitable to high drug concentration. Sterile injectablesolutions can be prepared by incorporating the active compound (i.e.,antibody, antibody portion, or other TNFα inhibitor) in the requiredamount in an appropriate solvent with one or a combination ofingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating theactive compound into a sterile vehicle that contains a basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum drying andfreeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. The proper fluidity of a solution can be maintained,for example, by the use of a coating such as lecithin, by themaintenance of the required particle size in the case of dispersion andby the use of surfactants. Prolonged absorption of injectablecompositions can be brought about by including in the composition anagent that delays absorption, for example, monostearate salts andgelatin.

In one embodiment, exemplary embodiments provide a wearable automaticinjection device, e.g., autoinjector pen, comprising an effective TNFαinhibitor and a pharmaceutically acceptable carrier. Thus, the inventionprovides a pre-fillable and/or pre-filled automatic injection devicecomprising a TNFα inhibitor.

In one embodiment, the antibody or antibody portion for use in themethods of the invention is incorporated into a pharmaceuticalformulation as described in PCT/IB03/04502 and U.S. Patent PublicationNo. 2004/0033228. This formulation includes a concentration 50 mg/ml ofthe antibody D2E7 (adalimumab), wherein a wearable automatic injectiondevice contains 40 mg of antibody for subcutaneous injection. In oneembodiment, the automatic injection device of the invention (or morespecifically the syringe of the device) comprises a formulation ofadalimumab having the following formula: adalimumab, sodium chloride,monobasic sodium phosphate dihydrate, dibasic sodium phosphatedihydrate, sodium citrate, citric acid monohydrate, mannitol,polysorbate 80 and water, e.g., water for injection. In anotherembodiment, the automatic injection device comprises a volume ofadalimumab including 40 mg adalimumab, 4.93 mg sodium chloride, 0.69 mgmonobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphatedihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6mg mannitol, 0.8 mg polysorbate 80 and water, e.g., water for injection.In one embodiment, sodium hydroxide is added as necessary to adjust pH.

The dose amount of TNFα inhibitor in the automatic injection device mayvary according to the disorder for which the TNFα inhibitor is beingused to treat. In one embodiment, the invention includes a wearableautomatic injection device comprising a dose of adalimumab of about 20mg of adalimumab; 40 mg of adalimumab; 80 mg of adalimumab; and 160 mgof adalimumab. It should be noted that for all ranges described herein,including the dose ranges, all numbers intermediary to the recitedvalues are included in the invention, e.g., 36 mg of adalimumab, 48 mgof adalimumab, etc. In addition ranges recited using said numbers arealso included, e.g. 40 to 80 mg of adalimumab. The numbers recitedherein are not intended to limit the scope of the invention.

The TNFα antibodies and inhibitors used in the invention may also beadministered in the form of protein crystal formulations that include acombination of protein crystals encapsulated within a polymeric carrierto form coated particles. The coated particles of the protein crystalformulation may have a spherical morphology and be microspheres of up to500 micro meters in diameter or they may have some other morphology andbe microparticulates. The enhanced concentration of protein crystalsallows the antibody of the invention to be delivered subcutaneously. Inone embodiment, the TNFα antibodies of the invention are delivered via aprotein delivery system, wherein one or more of a protein crystalformulation or composition, is administered to a patient with aTNFα-related disorder. Compositions and methods of preparing stabilizedformulations of whole antibody crystals or antibody fragment crystalsare also described in WO 02/072636, which is incorporated by referenceherein. In one embodiment, a formulation comprising the crystallizedantibody fragments described in International Patent Application No.PCT/IB03/04502 and U.S. Patent Publication No. 2004/0033228 is used totreat rheumatoid arthritis using the methods of the invention.

Supplementary active compounds can also be incorporated into thecompositions. In certain embodiments, an antibody or antibody portionfor use in the methods of the invention is co-formulated with and/orco-administered with one or more additional therapeutic agents,including a rheumatoid arthritis inhibitor or antagonist. For example,an anti-hTNFα antibody or antibody portion may be co-formulated and/orco-administered with one or more additional antibodies that bind othertargets associated with TNFα related disorders (e.g., antibodies thatbind other cytokines or that bind cell surface molecules), one or morecytokines, soluble TNFα receptor (see e.g., PCT Publication No. WO94/06476) and/or one or more chemical agents that inhibit hTNFαproduction or activity (such as cyclohexane-ylidene derivatives asdescribed in PCT Publication No. WO 93/19751) or any combinationthereof. Furthermore, one or more antibodies of the invention may beused in combination with two or more of the foregoing therapeuticagents. Such combination therapies may advantageously utilize lowerdosages of the administered therapeutic agents, thus avoiding possibleside effects, complications or low level of response by the patientassociated with the various monotherapies. Additional agents that may beused in combination with a TNFα antibody or antibody portion aredescribed in U.S. patent application Ser. No. 11/800,531, which isexpressly incorporated herein by reference in its entirety.

IX. INCORPORATION BY REFERENCE

The contents of all references, including patents and patentapplications, cited throughout this application are hereby incorporatedherein by reference in their entirety. The appropriate components andmethods of those references may be selected for the invention andembodiments thereof. Still further, the components and methodsidentified in the Background section are integral to this disclosure andcan be used in conjunction with or substituted for components andmethods described elsewhere in the disclosure within the scope of theinvention.

X. EQUIVALENTS

In describing exemplary embodiments, specific terminology is used forthe sake of clarity. For purposes of description, each specific term isintended to at least include all technical and functional equivalentsthat operate in a similar manner to accomplish a similar purpose.Additionally, in some instances where a particular exemplary embodimentincludes a plurality of system elements or method steps, those elementsor steps may be replaced with a single element or step. Likewise, asingle element or step may be replaced with a plurality of elements orsteps that serve the same purpose. Further, where parameters for variousproperties are specified herein for exemplary embodiments, thoseparameters may be adjusted up or down by 1/20th, 1/10th, ⅕th, ⅓rd, ½,etc., or by rounded-off approximations thereof, unless otherwisespecified. Moreover, while exemplary embodiments have been shown anddescribed with references to particular embodiments thereof, those ofordinary skill in the art will understand that various substitutions andalterations in form and details may be made therein without departingfrom the scope of the invention. Further still, other aspects, functionsand advantages are also within the scope of the invention.

Exemplary flowcharts are provided herein for illustrative purposes andare non-limiting examples of methods. One of ordinary skill in the artwill recognize that exemplary methods may include more or fewer stepsthan those illustrated in the exemplary flowcharts, and that the stepsin the exemplary flowcharts may be performed in a different order thanshown.

1. A wearable automatic injection device for providing a subcutaneousinjection of a therapeutic agent into a patient, the wearable automaticinjection device comprising: a housing comprising a patient contactportion securable to the patient; an injection assembly moveablydisposed in the housing holding a hypodermic injection needle forinsertion into the patient, the injection assembly moveable between aretracted position in which the injection needle does not protrudeoutside the housing and an extended position in which the injectionneedle protrudes outside the housing; a vessel provided in the housingfor holding the therapeutic agent; a plunger moveably disposed in thevessel for ejecting the therapeutic agent from the vessel into theinjection assembly; a plunger actuation mechanism for actuating theplunger within the vessel; a retraction trigger responsive to a changeof state of the wearable automatic injection device from an injectionstate to a post-injection state; and a retraction mechanism forautomatically retracting the injection assembly from the extendedposition in the injection state to the retracted position in thepost-injection state upon triggering by the retraction trigger.
 2. Thewearable automatic injection device of claim 1, wherein the housingfurther comprises: an interior portion defined by a plurality of wallsand defining at least one open end opposing the patient contact portion.3. The wearable automatic injection device of claim 1, furthercomprising: a cover portion covering the open end of the housing.
 4. Thewearable automatic injection device of claim 1, wherein the housing isprovided as a unitary cover coupled to a base that forms the patientcontact portion.
 5. The wearable automatic injective device of claim 1,wherein the housing is provided as a plurality of walls defining atleast one open end opposing the patient contact portion.
 6. The wearableautomatic injection device of claim 1, further comprising: an adhesivelayer provided on the patient contact portion of the housing forattaching the housing to the patient.
 7. The wearable automaticinjection device of claim 1, further comprising: an inspection windowdisposed in the housing that allows the user to inspect the therapeuticagent held by the vessel from outside the housing.
 8. The wearableautomatic injection device of claim 1, wherein the vessel comprises asyringe.
 9. The wearable automatic injection device of claim 8, whereinthe syringe comprises: a barrel portion for holding the therapeuticagent; and a syringe needle coupled to a distal end of the barrelportion for establishing fluid communication between the barrel portionof the syringe and the injection needle.
 10. The wearable automaticinjection device of claim 9, wherein the injection assembly comprises: aseptum that is pierceable by the syringe needle of the syringe; and afluid conduit extending between the injection needle and the septum,wherein piercing of the septum by the syringe needle of the syringecouples the barrel portion of the syringe and the injection needle. 11.The wearable automatic injection device of claim 10, wherein the syringeneedle of the syringe is spaced from the septum when the device is in apre-injection state, and wherein the syringe needle pierces the septumwhen the device is in the injection state.
 12. The wearable automaticinjection device of claim 1, wherein the vessel comprises a cartridge.13. The wearable automatic injection device of claim 12, wherein thecartridge comprises: a barrel portion for holding the therapeutic agent;and a septum that is pierceable by a piercing needle.
 14. The wearableautomatic injection device of claim 13, wherein the injection assemblycomprises: the piercing needle for establishing fluid communicationbetween the barrel portion of the cartridge and the injection needle;and a fluid conduit provided between the injection needle and thepiercing needle for establishing fluid communication between theinjection needle and the barrel portion of the cartridge.
 15. Thewearable automatic injection device of claim 14, wherein piercing of theseptum by the piercing needle of the injection assembly establishesfluid communication between the barrel portion of the cartridge and theinjection needle.
 16. The wearable automatic injection device of claim15, wherein the septum of the cartridge is spaced from the piercingneedle of the injection assembly when the device is in a pre-injectionstate, and wherein the piercing needle pierces the septum when thedevice is in the injection state.
 17. The wearable automatic injectiondevice of claim 1, wherein the vessel is moveably disposed within thehousing.
 18. The wearable automatic injection device of claim 17,wherein the vessel is moveable between a first position in apre-injection state and a second position in the injection state. 19.The wearable automatic injection device of claim 18, further comprising:a vessel actuator for automatically actuating the vessel from the firstposition to the second position.
 20. The wearable automatic injectiondevice of claim 19, wherein a fluid pathway is established between theinjection needle and the vessel when the injection assembly is in theextended position and the vessel is in the second position in theinjection state. 21-78. (canceled)